Macrolides and ketolides having antimicrobial activity

ABSTRACT

The present invention provides compounds having antimicrobial activity for preventing and treating diseases caused by microbial infections. Thus, the present invention relates to novel semi-synthetic 11,12-γ lactone macrolides and ketolides having antimicrobial activity, processes for making compounds as well as pharmaceutical compositions containing said compounds as active ingredients and methods of treating microbial infections with the compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of Application No.PCT/IB2007/002405, filed Aug. 22, 2007, published in English, whichclaims benefit of an Indian patent application No. 1336/MUM/2006, filedAug. 24, 2006. The entire disclosure of these prior applications arehereby incorporated by reference.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention has been created without the sponsorship or funding ofany federally sponsored research or development program.

FIELD OF THE INVENTION

The present invention relates to novel 11,12-γ lactone macrolides andketolides having antimicrobial activity, pharmaceutical compositionscontaining the compounds and methods of treating microbial infectionswith the compounds.

BACKGROUND OF THE INVENTION

Macrolides are a well-known family of antimicrobial agents, erythromycinA, 14-membered macrolide, was isolated in 1952 from Streptomyceserythraeus. Examples of macrolides being used as therapeutic agents areroxithromycin, clarithromycin and azithromycin (azalide). Ketolides aresemisynthetic 14-membered ring macrolide derivatives, characterized bythe presence of a keto function at position 3 instead of L-cladinosemoiety present in the macrolactone ring. Telithromycin and Cethromycinare examples of ketolides.

U.S. Pat. No. 4,331,803 discloses the 6-O-methyl derivative oferythromycin i.e. clarithromycin. The U.S. Pat. No. 4,349,545 disclosesroxithromycin. The azalide azithromycin is disclosed in U.S. Pat. No.4,517,359. Telithromycin is described in EP 680967 A1 and correspondingU.S. Pat. No. 5,635,485 and Bioorg. Med. Chem. Lett. 1999, 9(21),3075-3080. Another ketolide Cethromycin (ABT 773) is disclosed in WO98/09978, and J. Med. Chem. 2000, 43, 1045.

The U.S. Pat. No. 6,900,183 describes 11,12-γ lactone ketolides havingC-21 of the lactone substituted with cyano or amino derivatives.

The patent application US 2004/0077557 and PCT publications WO 02/16380,WO 03/42228 WO 04/16634 and WO 03/072588 discloses 11,12-γ lactoneketolides.

DESCRIPTION OF THE INVENTION

In one general aspect there is provided macrolide and ketolide compoundsof Formula I

and their pharmaceutically acceptable salts, pharmaceutically acceptablesolvates, polymorphs, enantiomers or diastereomers,wherein* indicates a chiral center;R₁ is hydrogen or methyl;R₂ is hydrogen or hydroxyl protecting group,

-   -   wherein hydroxyl protecting groups are selected from the group        consisting of triethylsilyl, trimethylsilyl, acetyl, benzoyl,        methoxymethyl, benzyl, methoxyethoxymethyl or        tertbutyldimethylsilyl;        Q is Het or

wherein

-   -   Het is selected from

-   -    wherein R₃ is one or more substituent selected from the group        consisting of NO₂, CN, halogen, C₁-C₆ alkyl, C₂-C₆ alkenyl,        CH₂CONH₂, CH₂CO₂Et, CH₂CN, CH₂CH₂OH, CH₂OCH₂CH₂OCH₃, NH₂,        substituted C₁-C₆ alkyl and substituted C₂-C₆ alkenyl;    -   T is selected from the group consisting of:        -   hydrogen, —(CH₂)_(m)—R₅, —(CH₂)_(m)—CH═CH—R₅,            —(CH₂)_(m)—C≡C—R₅, -A-(CH₂)_(m)—R₅, -A-(CH₂)_(m)—CH═CH—R₅,            -A-(CH₂)_(m)—C≡C—R₅, —(CH₂)_(m)—B—R₅, -A-(CH₂)_(m)—B—R₅,            —(CH₂)_(m)—X—R₆, —(CH₂)_(m)—B—X—R₆, —(CH₂)_(m)—CH═CH—X—R₆,            —(CH₂)_(m)—C≡C—X—R₆, -A-(CH₂)_(m)—X—R₆, -A-(CH₂)_(m)—B—X—R₆,            -A-(CH₂)_(m)—CH═CH—X—R₆ and -A-(CH₂)_(m)—C≡C—X—R₆;        -   wherein,            -   m is 0, 1, 2 or 3;            -   R₅ is selected from the group consisting of:                -   hydrogen, cyano, halogen, hydroxyl, CO₂(C₁-C₆                    alkyl), CO NR_(a)R_(b), NR_(a)R_(b), C₁-C₆ alkyl or                    substituted C₁-C₆ alkyl, C₂-C₆ alkenyl or                    substituted C₂-C₆ alkenyl, C₂-C₆ alkynyl or                    substituted C₂-C₆ alkynyl, 6 membered substituted or                    unsubstituted aryl, 5-6 membered substituted or                    unsubstituted heteroaryl, 3-6 membered substituted                    or unsubstituted cycloalkyl and 3-6 membered                    substituted or unsubstituted heterocyclyl;                -    wherein R_(a) and R_(b) are independently hydrogen,                    C₁-C₆ alkyl or R_(a) and R_(b) together with the                    nitrogen to which they are attached form a 5-6                    membered heterocyclic ring wherein the heterocycle                    has one or more heteroatoms selected from N, O, S;            -   A is —CO— or —CONH—;            -   B is —O—, —S—, —SO—, —SO₂—, —CO—, —CONH—, —CON(CH₃)—,                —NHCONH—, —C(NH₂)═N—O—,

-   -   -   -   -   wherein                -   R₈ is a substitutent at any one of carbon of the                    heterocycle, R₈ is selected from the group                    comprising of hydrogen, C₁-C₆ alkyl, substituted                    C₁-C₆ alkyl, C₂-C₆ alkenyl and substituted C₂-C₆                    alkenyl;

            -   X is a 6 membered aryl or a 5-6 membered heteroaryl;

            -   R₆ is aryl, heteroaryl, substituted aryl or substituted                heteroaryl;                Y′ is hydrogen and Y is OR₇, wherein R₇ is hydrogen or

-   -   wherein R₂ is hydrogen, (when R₂ is hydrogen, R₇ is designated        as cladinose) or hydroxyl protecting group,        -   wherein hydroxyl protecting groups are selected from the            group consisting of triethylsilyl, trimethylsilyl, acetyl,            benzoyl, methoxymethyl, methoxyethoxymethyl, benzyl or            tertbutyldimethylsilyl;            or            Y and Y′ together with the carbon to which they are attached            form C═O.

In one embodiment there is provided macrolide compound of Formula I-a,wherein,

wherein Q, R₁, R₂ and R_(2′) are as defined above.

Another embodiment relates to macrolide compound of Formula I-b,

wherein R₁ and Het are as defined above.

Another embodiment relates to compound of Formula I-c,

wherein T and R₁ are as defined above.

Another embodiment relates to ketolide compound of Formula I-d,

wherein R₁ is CH₃, R₂ and Q are as defined above.

Another embodiment relates to ketolide compound of the invention ofFormula I-e,

wherein Het is as defined above.

Another embodiment relates to ketolide compound of Formula I-f,

wherein T is as defined above.

Another embodiment relates to pharmaceutical compositions of compoundsof Formula I and their pharmaceutically acceptable salts,pharmaceutically acceptable solvates, polymorphs, enantiomers ordiastereomers, together with one or more pharmaceutically acceptablecarriers, excipients or diluents, for the treatment and prevention of amicrobial infection in human or animal.

In another embodiment the compounds of Formula I and theirpharmaceutically acceptable salts, pharmaceutically acceptable solvates,polymorphs, enantiomers or diastereomers.

Yet another embodiment is also directed to a method of treating asubject having a condition caused by or contributed to by microbialinfection, which comprises administering to the said subject atherapeutically effective amount of compound of Formula I and theirpharmaceutically acceptable salts, pharmaceutically acceptable solvates,polymorphs, enantiomers or diastereomers.

Another embodiment is further directed to a method of preventing asubject from suffering from a condition caused by or contributed to bymicrobial infection, which comprises administering to the subject aprophylactically effective amount of compound of Formula I and theirpharmaceutically acceptable salts, pharmaceutically acceptable solvates,polymorphs, enantiomers or diastereomers.

Another embodiment relates to method of preparation of the compounds ofFormula I and their pharmaceutically acceptable salts, pharmaceuticallyacceptable solvates, polymorphs, enantiomers or diastereomers.

Other objects and advantages will become apparent to those skilled inthe art from a review of the ensuing specification.

Representative compounds of the invention are

-   Compound of Formula I-b where Het is 1H-tetrazol-5-yl, R₁ is CH₃;-   Compound of Formula I-b where Het is    2-(2-methoxy-ethoxymethyl)-2H-tetrazol-5-yl, R₁ is CH₃;-   Compound of Formula I-b where Het is    1-(2-methoxy-ethoxymethyl)-2H-tetrazol-5-yl, R₁ is CH₃;-   Compound of Formula I-b where Het is    2-(ethoxycarbonylmethyl)-2H-tetrazol-5-yl, R₁ is CH₃;-   Compound of Formula I-b where Het is    1-(ethoxycarbonylmethyl)-2H-tetrazol-5-yl, R₁ is CH₃;-   Compound of Formula I-b where Het is    2-(carbamoylmethyl)-2H-tetrazol-5-yl, R₁ is CH₃;-   Compound of Formula I-b where Het is    1-(carbamoylmethyl)-2H-tetrazol-5-yl, R₁ is CH₃;-   Compound of Formula I-b where Het is    2-(cyanomethyl)-2H-tetrazol-5-yl, R₁ is CH₃;-   Compound of Formula I-b where Het is    1-(cyanomethyl)-2H-tetrazol-5-yl, R₁ is CH₃;-   Compound of Formula I-b where Het is 2-(allyl)-2H-tetrazol-5-yl, R₁    is CH₃;-   Compound of Formula I-b where Het is 1-(allyl)-2H-tetrazol-5-yl, R₁    is CH₃;-   Compound of Formula I-b where Het is    2-(hydroxyethyl)-2H-tetrazol-5-yl, R₁ is CH₃;-   Compound of Formula I-b where Het is    1-(hydroxyethyl)-2H-tetrazol-5-yl, R₁ is CH₃;-   Compound of Formula I-b where Het is 2-(carboxylic    acid(3-fluoro-phenyl)-methylamide)-2H-tetrazol-5-yl, R₁ is CH₃;-   Compound of Formula I-b where Het is 5-methyl-[1,2,4]oxadiazol-3-yl,    R₁ is CH₃;-   Compound of Formula I-b where Het is 4,5-dihydro-1H-imidazol-2-yl,    R₁ is CH₃;-   Compound of Formula I-b where Het is    1,4,5,6-tetrahydro-pyrimidin-2-yl, R₁ is CH₃;

-   Compound of Formula I-c where T is H, R₁ is CH₃;-   Compound of Formula I-c where T is CO(CH₂)₂-(pyridin-3-yl), R₁ is    CH₃;-   Compound of Formula I-c where T is COCH₂O-(2-chlorophenyl), R₁ is    CH₃;-   Compound of Formula I-c where T is CO(CH₂)₂-(4-dimethylamino)phenyl,    R₁ is CH₃;-   Compound of Formula I-c where T is CO-(pyridin-3-yl), R₁ is CH₃;-   Compound of Formula I-c where T is CO(CH₂)₂-(pyridin-4-yl), R₁ is    CH₃;-   Compound of Formula I-c where T is CO(CH₂)₂-(3-methoxy)phenyl, R₁ is    CH₃;-   Compound of Formula I-c where T is CO(CH₂)₂-(4-methoxy)phenyl, R₁ is    CH₃;-   Compound of Formula I-c where T is CO(CH₂)₂-(3-cyano)phenyl, R₁ is    CH₃;-   Compound of Formula I-c where T is CO(CH₂)₂-(4-cyano)phenyl, R₁ is    CH₃;-   Compound of Formula I-c where T is COCH₂O-(3-chloro)phenyl, R₁ is    CH₃;-   Compound of Formula I-c where T is CO(CH₂)₂-(3,5-dimethoxy)phenyl,    R₁ is CH₃;-   Compound of Formula I-c where T is CO(CH₂)₂-(2,3-dimethoxy)phenyl,    R₁ is CH₃;-   Compound of Formula I-c where T is CO(CH₂)₂-(2,5-dimethoxy)phenyl,    R₁ is CH₃;-   Compound of Formula I-c where T is CO(CH₂)₂-(3-fluoro)phenyl, R₁ is    CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(4-trifluoromethyl)phenyl, R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(4-(4-methyl-piperazine)phenyl), R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(4-(2-methylphenyl)-piperazinyl), R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(4-(2-methoxyphenyl)-piperazinyl), R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(4-(3-methoxyphenyl)-piperazinyl), R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(4-(2-fluorophenyl)-piperazinyl), R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(4-(pyrimidin-2-yl)-piperazinyl), R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(4-(pyridin-2-yl)-piperazinyl), R₁ is CH₃;-   Compound of Formula I-c where T is COCH₂O-phenyl, R₁ is CH₃;-   Compound of Formula I-c where T is COCH₂O-(2-methylphenyl), R₁ is    CH₃;-   Compound of Formula I-c where T is COCH₂O-(3-methylphenyl), R₁ is    CH₃;-   Compound of Formula I-c where T is COCH₂O-(4-methylphenyl), R₁ is    CH₃;-   Compound of Formula I-c where T is COCH₂O-(2-methoxyphenyl), R₁ is    CH₃;-   Compound of Formula I-c where T is COCH₂O-(4-methoxyphenyl), R₁ is    CH₃;-   Compound of Formula I-c where T is    COCH₂O-(2,3,4,5,6-pentafluorophenyl), R₁ is CH₃;-   Compound of Formula I-c where T is COCH₂O-(4-cyanophenyl), R₁ is    CH₃;-   Compound of Formula I-c where T is CO(CH₂)₂-(4-(phenyl)piperazinyl),    R₁ is CH₃;-   Compound of Formula I-c where T is COCH₂S-phenyl, R₁ is CH₃;-   Compound of Formula I-c where T is COCH₂S-(4-fluorophenyl), R₁ is    CH₃;-   Compound of Formula I-c where T is COCH₂S-(2-fluorophenyl), R₁ is    CH₃;-   Compound of Formula I-c where T is COCH₂S-(3-fluorophenyl), R₁ is    CH₃;-   Compound of Formula I-c where T is COCH₂S-(3-methoxyphenyl), R₁ is    CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(4-([1,2,3]-triazol-1-yl)phenyl), R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(4-(imidazol-1-yl)phenyl), R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(4-([1,2,4]-triazol-1-yl)phenyl), R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(4-(4-acetyl-[1,2,3]triazol-1-yl))-phenyl, R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(4-(4-cyano-[1,2,4]-triazol-1-yl)phenyl), R₁ is CH₃;-   Compound of Formula I-c where T is CO(CH₂)₂-(benzo[1,3]dioxol-5-yl),    R₁ is CH₃;-   Compound of Formula I-c where T is COCH₂-(benzo[1,3]dioxol-5-yl), R₁    is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(1-(4-methoxyphenyl)-1H-[1,2,3]triazol-4-yl), R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(1-(pyridin-3-yl)-1H-[1,2,3]triazol-4-yl), R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(1-(4-fluorophenyl)-1H-[1,2,3]triazol-4-yl), R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(1-(3-methylphenyl)-1H-[1,2,3]triazol-4-yl), R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(1-(3-chlorophenyl)-1H-[1,2,3]triazol-4-yl), R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(1-(2-fluorophenyl)-1H-[1,2,3]triazol-4-yl), R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(1-(2,4-difluorophenyl)-1H-[1,2,3]triazol-4-yl), R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(1-(3,4-difluorophenyl)-1H-[1,2,3]triazol-4-yl), R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(1-(2,3,4-trifluorophenyl)-1H-[1,2,3]triazol-4-yl), R₁ is    CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(1-(2-fluoro-4-methyl-phenyl)-1H-[1,2,3]triazol-4-yl), R₁    is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(1-(2-fluoro-4-methoxy-phenyl)-1H-[1,2,3]triazol-4-yl), R₁    is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(1-(2,3-difluoro-4-ethoxy-phenyl)-1H-[1,2,3]triazol-4-yl),    R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl), R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(3-(3-bromo-phenyl)-[1,2,4]oxadiazol-5-yl), R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(3-(4-nitro-phenyl)-[1,2,4]oxadiazol-5-yl), R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(3-(3-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl), R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl), R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(3-(3-methoxy-phenyl)-[1,2,4]oxadiazol-5-yl), R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(3-(3,5-dimethoxy-phenyl)-[1,2,4]oxadiazol-5-yl), R₁ is    CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(3-(4-chloro-phenyl)-[1,2,4]oxadiazol-5-yl), R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(3-(4-bromo-phenyl)-[1,2,4]oxadiazol-5-yl), R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(3-(pyridin-4-yl)-[1,2,4]oxadiazol-5-yl), R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(3-(pyridin-3-yl)-[1,2,4]oxadiazol-5-yl), R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(3-(2-fluoro-5-methoxy-phenyl)-[1,2,4]oxadiazol-5-yl), R₁    is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(3-phenyl-4H-imidazol-1-yl), R₁ is CH₃;-   Compound of Formula I-c where T is CO(CH₂)₂CONH-(4-methoxy-phenyl),    R₁ is CH₃;-   Compound of Formula I-c where T is CO(CH₂)₂CONH-(3-methoxy-phenyl),    R₁ is CH₃;-   Compound of Formula I-c where T is CO(CH₂)₂CONH-(2-methoxy-phenyl),    R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂CONH-(2,4-difluorophenyl), R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂CO-(4-(3-fluoro-phenyl)piperazin-1-yl), R₁ is CH₃;-   Compound of Formula I-c where T is CH₂CH₂CH₃, R₁ is CH₃;-   Compound of Formula I-c where T is CH₂CH₂OH, R₁ is CH₃;-   Compound of Formula I-c where T is CH₂CH₂OC₂H₅, R₁ is CH₃;-   Compound of Formula I-c where T is CH₂CH₂CH(CH₃)₂, R₁ is CH₃;-   Compound of Formula I-c where T is CH₂CH(CH₃)₂, R₁ is CH₃;-   Compound of Formula I-c where T is CH₂(CH₂)₂-phenyl, R₁ is CH₃;-   Compound of Formula I-c where T is CH₂-phenyl, R₁ is CH₃;-   Compound of Formula I-c where T is CH₂-(4-nitro)-phenyl, R₁ is CH₃;-   Compound of Formula I-c where T is CH₂-(4-bromo)-phenyl, R₁ is CH₃;-   Compound of Formula I-c where T is CH₂-(2-fluoro)-phenyl, R₁ is CH₃;-   Compound of Formula I-c where T is CH₂-(3,5-difluoro)-phenyl, R₁ is    CH₃;-   Compound of Formula I-c where T is CH₂-(2,4-difluoro)-phenyl, R₁ is    CH₃;-   Compound of Formula I-c where T is CH₂-(4-methyl)-phenyl, R₁ is CH₃;-   Compound of Formula I-c where T is CH₂-(3-methoxy)-phenyl, R₁ is    CH₃;-   Compound of Formula I-c where T is CH₂-(2-methyl)-phenyl, R₁ is CH₃;-   Compound of Formula I-c where T is    CH₂CH₂-(4-(pyridin-2-yl)piperazinyl), R₁ is CH₃;-   Compound of Formula I-c where T is    CH₂CH₂-(1-(3-methoxy)phenyl-1H-[1,2,3]triazol-4-yl), R₁ is CH₃;-   Compound of Formula I-c where T is    CH₂-(1-(4-methoxy-2-fluoro-phenyl)-1H-[1,2,3]triazol-4-yl), R₁ is    CH₃;-   Compound of Formula I-c where T is    CH₂-(5-methyl-[1,2,4]oxadiazol-3-yl), R₁ is CH₃;-   Compound of Formula I-c where T is    CH₂-(3-(5-fluoro-2-methoxyphenyl)-isoxazol-5-yl), R₁ is CH₃;-   Compound of Formula I-c where T is CH₂CH═CH₂, R₁ is CH₃;-   Compound of Formula I-c where T is CH₂CH₂CH═CH₂, R₁ is CH₃;-   Compound of Formula I-c where T is CH₂CH═CH-phenyl, R₁ is CH₃;-   Compound of Formula I-c where T is CH₂CH═CH-(2-methoxy)phenyl, R₁ is    CH₃;-   Compound of Formula I-c where T is CH₂CH═CH-(3-fluoro)phenyl, R₁ is    CH₃;-   Compound of Formula I-c where T is CH₂CH═CH-(4-cyano)phenyl, R₁ is    CH₃;-   Compound of Formula I-c where T is CH₂C(CH₃)═CH₂, R₁ is CH₃;-   Compound of Formula I-c where T is CH₂CH═C(CH₃)₂, R₁ is CH₃;-   Compound of Formula I-c where T is CH₂CH═CH-(3-cyano)phenyl, R₁ is    CH₃;-   Compound of Formula I-c where T is CH₂CH═CH-(3-acetoxy)phenyl, R₁ is    CH₃;-   Compound of Formula I-c where T is CH₂CH═CH-(3-hydroxymethyl)phenyl,    R₁ is CH₃;-   Compound of Formula I-c where T is    CH₂CH═CH-(4-trifluoromethyl)phenyl, R₁ is CH₃;-   Compound of Formula I-c where T is    CH₂CH═CH-(3-trifluoromethyl)phenyl, R₁ is CH₃;-   Compound of Formula I-c where T is    CH₂CH═CH-(2,3-dihydro-benzo[1,4]dioxin-6-yl), R₁ is CH₃;-   Compound of Formula I-c where T is CH₂CN, R₁ is CH₃;-   Compound of Formula I-c where T is CH₂C(NH₂)═N—OH, R₁ is CH₃;-   Compound of Formula I-c where T is CH₂C≡CH, R₁ is CH₃;-   Compound of Formula I-c where T is CH₂C≡C-phenyl, R₁ is CH₃;-   Compound of Formula I-c where T is CH₂C≡C-(3-cyano)phenyl, R₁ is    CH₃;-   Compound of Formula I-c where T is CH₂C≡C-(3-methyl)phenyl, R₁ is    CH₃;-   Compound of Formula I-c where T is COCH═CH-phenyl, R₁ is CH₃;-   Compound of Formula I-c where T is CO(CH₂)₂-phenyl, R₁ is CH₃;-   Compound of Formula I-c where T is COCH═CH-(pyridin-4-yl), R₁ is    CH₃;-   Compound of Formula I-c where T is COCH═CH-(pyridin-3-yl), R₁ is    CH₃;-   Compound of Formula I-c where T is COCH═CH-(pyridin-2-yl), R₁ is    CH₃;-   Compound of Formula I-c where T is    COCH═CH-(1-(2-methoxy-phenyl)-1H-[1,2,3]triazol-4-yl), R₁ is CH₃;-   Compound of Formula I-c where T is    COCH═CH-(1-(3-methoxy-phenyl)-1H-[1,2,3]triazol-4-yl), R₁ is CH₃;-   Compound of Formula I-c where T is    COCH═CH-(1-(4-methoxy-phenyl)-1H-[1,2,3]triazol-4-yl), R₁ is CH₃;-   Compound of Formula I-c where T is    COCH═CH-(1-(4-fluoro-phenyl)-1H-[1,2,3]triazol-4-yl), R₁ is CH₃;-   Compound of Formula I-c where T is    COCH═CH-(1-(3-fluoro-phenyl)-1H-[1,2,3]triazol-4-yl), R₁ is CH₃;-   Compound of Formula I-c where T is COCH₂NHCONH-phenyl, R₁ is CH₃;-   Compound of Formula I-c where T is COCH₂NHCONH-(4-fluorophenyl), R₁    is CH₃;-   Compound of Formula I-c where T is    COCH₂NHCONH-(3-chloro-4-methylphenyl), R₁ is CH₃;-   Compound of Formula I-c where T is CH₂CONH₂, R₁ is CH₃;-   Compound of Formula I-c where T is CH₂CONH-phenyl, R₁ is CH₃;-   Compound of Formula I-c where T is CH₂CONH-(3-fluoro)phenyl, R₁ is    CH₃;-   Compound of Formula I-c where T is CH₂CONH-(2-fluoro)phenyl, R₁ is    CH₃;-   Compound of Formula I-c where T is CH₂CONH-(4-fluoro)phenyl, R₁ is    CH₃;-   Compound of Formula I-c where T is CH₂CONH-(2,4-difluoro)phenyl, R₁    is CH₃;-   Compound of Formula I-c where T is CH₂CONH-(3,4-difluoro)phenyl, R₁    is CH₃;-   Compound of Formula I-c where T is CH₂CONH-(2,3,4-trifluoro)phenyl,    R₁ is CH₃;-   Compound of Formula I-c where T is CH₂CONH-(3-chloro)phenyl, R₁ is    CH₃;-   Compound of Formula I-c where T is CH₂CONH-(2-methoxy)phenyl, R₁ is    CH₃;-   Compound of Formula I-c where T is CH₂CONH-(3-methoxy)phenyl, R₁ is    CH₃;-   Compound of Formula I-c where T is CH₂CONH-(3,5-dimethoxy)phenyl, R₁    is CH₃;-   Compound of Formula I-c where T is CH₂CONH-cyclopropyl, R₁ is CH₃;-   Compound of Formula I-c where T is CH₂CON(CH₃)-(3-fluoro)phenyl, R₁    is CH₃;-   Compound of Formula I-c where T is CH₂CON(CH₃)-(4-chloro)phenyl, R₁    is CH₃;-   Compound of Formula I-c where T is    CH₂CONH-(6-pyrazol-1-yl-pyridin-3-yl), R₁ is CH₃;-   Compound of Formula I-c where T is    CH₂CONH-(3-(pyrazol-1-yl)-pyridin-5-yl), R₁ is CH₃;-   Compound of Formula I-c where T is    CH₂-(1-(4-fluorophenyl)-1H-[1,2,3]-triazol-5-yl), R₁ is CH₃;-   Compound of Formula I-c where T is    CH₂-(1-(3-fluorophenyl)-1H-[1,2,3]-triazol-5-yl), R₁ is CH₃;-   Compound of Formula I-c where T is CH₂-(1-(3,5-difluoro    phenyl)-1H-[1,2,3]-triazol-5-yl), R₁ is CH₃;-   Compound of Formula I-c where T is CH₂-(1-(3,4-difluoro    phenyl)-1H-[1,2,3]-triazol-5-yl), R₁ is CH₃;-   Compound of Formula I-c where T is CH₂-(1-(3,4,5-trifluoro    phenyl)-1H-[1,2,3]-triazol-5-yl), R₁ is CH₃;-   Compound of Formula I-c where T is    CH₂-(1-(3-chlorophenyl)-1H-[1,2,3]-triazol-5-yl), R₁ is CH₃;-   Compound of Formula I-c where T is    CH₂-(5-(pyridin-3-yl)-[1,2,4]-oxadiazol-3-yl), R₁ is CH₃;-   Compound of Formula I-c where T is CH₂CO₂CH₂CH₃, R₁ is CH₃;-   Compound of Formula I-c where T is CONH-phenyl, R₁ is CH₃;-   Compound of Formula I-c where T is CONH-(4-ethyl-phenyl), R₁ is CH₃;-   Compound of Formula I-c where T is CH₂CO-(4-(phenyl)-piperazinyl),    R₁ is CH₃;-   Compound of Formula I-c where T is    CH₂CO-(4-(2-fluorophenyl)-piperazinyl), R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂CO-(4-phenyl)-piperazinyl, R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-[3-(4-methoxy-phenyl)-[1,2,4]oxadiazol-5-yl], R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(1-pyridin-3-yl-1H-[1,2,3]-triazol-4yl), R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(1-(2-methoxy)phenyl)-1H-[1,2,3]triazol-4-yl), R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(1-(3-fluorophenyl)-1H-[1,2,3]triazol-4-yl), R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(3-phenyl-[1,2,4]oxadiazol-5-yl), R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(3-naphthalen-2-yl-[1,2,4]oxadiazol-5-yl), R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(1-(pyridin-3-yl)-[1,2,4]oxadiazol-5-yl), R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(1-(3,5-difluoro-phenyl)-1H-[1,2,3]triazol-4-yl), R₁ is    CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(1-(3,4-difluoro-phenyl)-1H-[1,2,3]triazol-4-yl), R₁ is    CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(4-(2-methoxy-phenyl)-piperazine-1-yl), R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(1-(3,5-dimethoxy-phenyl)-1H-[1,2,3]triazol-4-yl), R₁ is    CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(1-(3-methoxy-phenyl)-1H-[1,2,3]triazol-4-yl), R₁ is CH₃;-   Compound of Formula I-c where T is    CO(CH₂)₂-(3-(2-fluoro-5-methoxy-phenyl)-[1,2,4]oxadiazol-5-yl), R₁    is CH₃;

-   Compound of Formula I-e where Het is 1H-tetrazol-5-yl;-   Compound of Formula I-e where Het is 5-methyl-[1,2,4]oxadiazol-3-yl;-   Compound of Formula I-e where Het is 4,5-dihydro-1H-imidazol-2-yl;-   Compound of Formula I-e where Het is    1,4,5,6-tetrahydro-pyrimidin-2-yl;-   Compound of Formula I-e where Het is    2-(2-methoxy-ethoxy)-2H-tetrazol-5-yl;-   Compound of Formula I-e where Het is    1-(2-methoxy-ethoxy)-1H-tetrazol-5-yl;-   Compound of Formula I-e where Het is [1,2,4]-oxadiazol-3yl;-   Compound of Formula I-e where Het is    (5-trifluoromethyl)-[1,2,4]-oxadiazol-3yl;-   Compound of Formula I-e where Het is (4,5)-dihydro-1H-imidazol-2-yl;-   Compound of Formula I-e where Het is 1-(allyl)-1H-tetrazol-5-yl-   Compound of Formula I-e where Het is 2-(allyl)-2H-tetrazol-5-yl

-   Compound of Formula I-f where T is H;-   Compound of Formula I-f where T is CH₃;-   Compound of Formula I-f where T is CH₂CH₂CH₃;-   Compound of Formula I-f where T is CH₂CN;-   Compound of Formula I-f where T is CH₂OCH₂CH₂OCH₃;-   Compound of Formula I-f where T is CH₂CH₂CH(CH₃)₂;-   Compound of Formula I-f where T is CH₂-cyclopropyl;-   Compound of Formula I-f where T is CH₂CH═CH₂;-   Compound of Formula I-f where T is CH₂C(═CH₂)CH₃;-   Compound of Formula I-f where T is CH₂CH═C(CH₃)₂;-   Compound of Formula I-f where T is CH₂CH═CHCH₃;-   Compound of Formula I-f where T is CH₂C(F)═CH₂;-   Compound of Formula I-f where T is CH₂CH═CH-phenyl;-   Compound of Formula I-f where T is CH₂CH═CH-(3-fluoro)phenyl;-   Compound of Formula I-f where T is CH₂CH═CH-(3-chloro)phenyl;-   Compound of Formula I-f where T is    CH₂CH═CH-(3-trifluoromethyl)phenyl;-   Compound of Formula I-f where T is    CH₂CH═CH-(2-trifluoromethyl)phenyl;-   Compound of Formula I-f where T is CH₂CH═CH-(pyridin-3-yl);-   Compound of Formula I-f where T is CH₂CH═CH-(pyrimidin-5-yl);-   Compound of Formula I-f where T is CH₂C≡CH;-   Compound of Formula I-f where T is CH₂C≡C-phenyl;-   Compound of Formula I-f where T is CH₂C≡C-(3-cyano)phenyl;-   Compound of Formula I-f where T is CH₂C≡C-(3-methyl)phenyl;-   Compound of Formula I-f where T is CH₂C≡C-(3-fluoro)phenyl;-   Compound of Formula I-f where T is CH₂C≡C-(3-chloro)phenyl;-   Compound of Formula I-f where T is CH₂C≡C-(3-methoxy)phenyl;-   Compound of Formula I-f where T is CH₂C≡C-(pyridin-2-yl);-   Compound of Formula I-f where T is CH₂C≡C-(2-chloropyridin-5-yl);-   Compound of Formula I-f where T is CH₂C≡C-(2-fluoropyridin-5-yl);-   Compound of Formula I-f where T is CH₂C≡C-(pyridin-3-yl);-   Compound of Formula I-f where T is CH₂-phenyl;-   Compound of Formula I-f where T is CH₂(CH₂)₂-phenyl;-   Compound of Formula I-f where T is CH₂-(4-methoxyphenyl);-   Compound of Formula I-f where T is CH₂-(3-chlorophenyl);-   Compound of Formula I-f where T is CH₂-(3-methoxyphenyl);-   Compound of Formula I-f where T is CH₂-(2-fluorophenyl);-   Compound of Formula I-f where T is CH₂-(4-(isopropyl)phenyl);-   Compound of Formula I-f where T is    CH₂-(4-(1H-[1,2,4]-triazol)phenyl);-   Compound of Formula I-f where T is CH₂-(4-(pyrimidin-5-yl)phenyl);-   Compound of Formula I-f where T is CH₂-(4-(pyridin-2-yl)phenyl);-   Compound of Formula I-f where T is    CH₂-(5-phenyl[1,3,4]oxadiazol-2-yl);-   Compound of Formula I-f where T is    CH₂-(5-(pyridin-3-yl)[1,3,4]oxadiazol-2-yl);-   Compound of Formula I-f where T is    CH₂-(5-(3-fluorophenyl)[1,3,4]oxadiazol-2-yl);-   Compound of Formula I-f where T is    CH₂-(5-(4-methoxyphenyl)[1,3,4]oxadiazol-2-yl);-   Compound of Formula I-f where T is    CH₂-(5-(pyridin-2-yl)[1,3,4]oxadiazol-2-yl);-   Compound of Formula I-f where T is    CH₂-(5-(pyrazin-2-yl)[1,3,4]oxadiazol-2-yl);-   Compound of Formula I-f where T is    CH₂-(5-(3,5-dimethoxyphenyl)[1,3,4]oxadiazol-2-yl);-   Compound of Formula I-f where T is    CH₂-(5-(pyrimidin-2-yl)[1,3,4]oxadiazol-2-yl);-   Compound of Formula I-f where T is    CH₂-(5-(6-methoxy-pyridin-2-yl)[1,3,4]oxadiazol-2-yl);-   Compound of Formula I-f where T is    CH₂-((5-cyclopropyl)-[1,3,4]oxadiazol-2-yl);-   Compound of Formula I-f where T is    CH₂-(5-(5-methyl-pyridin-2-yl)[1,3,4]oxadiazol-2-yl);-   Compound of Formula I-f where T is    CH₂-(5-(5-cyclopropyl-pyridin-2-yl)[1,3,4]oxadiazol-2-yl)-   Compound of Formula I-f where T is    CH₂-(5-(5-cyano-pyridin-2-yl)[1,3,4]oxadiazol-2-yl);-   Compound of Formula I-f where T is    CH₂-(5-(5-dimethylamino-pyridin-2-yl)[1,3,4]oxadiazol-2-yl);-   Compound of Formula I-f where T is CH₂-(5-(5-methoxy-pyridin-2-yl)    [1,3,4]oxadiazol-2-yl);-   Compound of Formula I-f where T is    CH₂-(5-(5-fluoro-pyridin-2-yl)[1,3,4]oxadiazol-2-yl);-   Compound of Formula I-f where T is    CH₂-(5-(5-chloro-pyridin-2-yl)[1,3,4]oxadiazol-2-yl);-   Compound of Formula I-f where T is    CH₂-(5-(pyrimidin-5-yl)[1,3,4]oxadiazol-2-yl);-   Compound of Formula I-f where T is    CH₂-(3-phenyl[1,2,4]oxadiazol-5-yl);-   Compound of Formula I-f where T is    CH₂-(3-(3-fluorophenyl)[1,2,4]oxadiazol-5-yl);-   Compound of Formula I-f where T is    CH₂-(3-(3-chlorophenyl)[1,2,4]oxadiazol-5-yl);-   Compound of Formula I-f where T is    CH₂-(3-(4-chlorophenyl)[1,2,4]oxadiazol-5-yl);-   Compound of Formula I-f where T is    CH₂-(3-(4-methoxyphenyl)[1,2,4]oxadiazol-5-yl);-   Compound of Formula I-f where T is    CH₂-(3-(3,5-dimethoxyphenyl)[1,2,4]oxadiazol-5-yl);-   Compound of Formula I-f where T is    CH₂-(3-(pyridin-3-yl)[1,2,4]oxadiazol-5-yl);-   Compound of Formula I-f where T is    CH₂-(3-(pyridin-2-yl)[1,2,4]oxadiazol-5-yl);-   Compound of Formula I-f where T is    CH₂-(3-(pyrimidin-2-yl)[1,2,4]oxadiazol-5-yl);-   Compound of Formula I-f where T is    CH₂-(3-cyclopropyl[1,2,4]oxadiazol-5-yl);-   Compound of Formula I-f where T is    CH₂-(3-(6-methylpyridin-2-yl)[1,2,4]oxadiazol-5-yl);-   Compound of Formula I-f where T is    CH₂-(3-(3-methylpyridin-2-yl)[1,2,4]oxadiazol-5-yl);-   Compound of Formula I-f where T is    CH₂-(5-methyl[1,2,4]oxadiazol-3-yl);-   Compound of Formula I-f where T is    CH₂-(5-phenyl[1,2,4]oxadiazol-3-yl);-   Compound of Formula I-f where T is    CH₂-(5-(3-fluorophenyl)[1,2,4]oxadiazol-3-yl);-   Compound of Formula I-f where T is    CH₂-(5-(3-chlorophenyl)[1,2,4]oxadiazol-3-yl);-   Compound of Formula I-f where T is    CH₂-(5-(3-fluoro-4-methoxyphenyl)[1,2,4]oxadiazol-3-yl);-   Compound of Formula I-f where T is    CH₂-(5-(3-cyanophenyl)[1,2,4]oxadiazol-3-yl);-   Compound of Formula I-f where T is    CH₂-(5-(pyridin-3-yl)[1,2,4]oxadiazol-3-yl);-   Compound of Formula I-f where T is    CH₂-(5-(pyrazin-2-yl)[1,2,4]oxadiazol-3-yl);-   Compound of Formula I-f where T is    CH₂-(5-(pyridin-2-yl)[1,2,4]oxadiazol-3-yl);-   Compound of Formula I-f where T is    CH₂-(5-(pyridin-4-yl)[1,2,4]oxadiazol-3-yl);-   Compound of Formula I-f where T is    CH₂-(5-(2-chloropyridin-3-yl)[1,2,4]oxadiazol-3-yl);-   Compound of Formula I-f where T is    CH₂-(5-(2-methoxypyridin-3-yl)[1,2,4]oxadiazol-3-yl);-   Compound of Formula I-f where T is    CH₂-(5-(2-fluoropyridin-3-yl)[1,2,4]oxadiazol-3-yl);-   Compound of Formula I-f where T is    CH₂-(5-cyclopropyl[1,2,4]oxadiazol-3-yl);-   Compound of Formula I-f where T is    CH₂-(5-(6-methylpyridin-2-yl)[1,2,4]oxadiazol-3-yl);-   Compound of Formula I-f where T is    CH₂-(5-methyl[1,2,4]oxadiazol-3-yl);-   Compound of Formula I-f where T is    CH₂-(5-trifluoromethyl[1,2,4]oxadiazol-3-yl);-   Compound of Formula I-f where T is    CH₂-(5-(pyridazin-2-yl)-[1,2,4]oxadiazol-3-yl);-   Compound of Formula I-f where T is    CH₂-(5-(2-methyl-oxazol-4-yl)-[1,2,4]oxadiazol-3-yl);-   Compound of Formula I-f where T is    CH₂-(5-(2-methyl-thiazol-4-yl)-[1,2,4]oxadiazol-3-yl);-   Compound of Formula I-f where T is    CH₂-(5-(pyrimidin-2-yl)-[1,2,4]oxadiazol-3-yl);-   Compound of Formula I-f where T is    CH₂-(3-(pyridin-3-yl)-isoxazol-5-yl);-   Compound of Formula I-f where T is    CH₂-(3-(3-fluorophenyl)-isoxazol-5-yl);-   Compound of Formula I-f where T is    CH₂-(3-(3-chlorophenyl)-isoxazol-5-yl);-   Compound of Formula I-f where T is    CH₂-(3-(4-fluorophenyl)-isoxazol-5-yl);-   Compound of Formula I-f where T is    CH₂-(3-(pyridin-2-yl)-isoxazol-5-yl);-   Compound of Formula I-f where T is    CH₂-(3-(3-methoxyphenyl)-isoxazol-5-yl);-   Compound of Formula I-f where T is CH₂-(3-phenyl-isoxazol-5-yl);-   Compound of Formula I-f where T is CH₂-(3-methyl-isoxazol-5-yl);-   Compound of Formula I-f where T is    CH₂-(3-(6-methoxy-pyridin-2-yl)-isoxazol-5-yl);-   Compound of Formula I-f where T is    CH₂-(3-(2-methoxy-pyridin-5-yl)-isoxazol-5-yl);-   Compound of Formula I-f where T is CH₂CONH₂;-   Compound of Formula I-f where T is CH₂CON(CH₃)₂;-   Compound of Formula I-f where T is CH₂CONH-(cyclopropyl);-   Compound of Formula I-f where T is CH₂CONH-(3-chloro-phenyl);-   Compound of Formula I-f where T is CH₂CONH-(3-fluoro-phenyl);-   Compound of Formula I-f where T is CH₂CO-(4-phenylpiperazin-1yl);-   Compound of Formula I-f where T is CO(CH₂)₂-(3-fluorophenyl);-   Compound of Formula I-f where T is CO(CH₂)₂-(4-methoxyphenyl);-   Compound of Formula I-f where T is CO(CH₂)₂-(2,3-dimethoxyphenyl);-   Compound of Formula I-f where T is    CO(CH₂)₂-(3-(3-fluorophenyl)-[1,2,4]oxadiazol-5-yl);-   Compound of Formula I-f where T is CONH-(4-ethylphenyl);-   Compound of Formula I-f where T is    CH₂-(3-(5-methylpyridin-2-yl)[1,2,4]oxadiazol-5-yl);-   Compound of Formula I-f where T is    CH₂-(3-(5-cyclopropyl-pyridin-2-yl)[1,2,4]oxadiazol-5-yl);-   Compound of Formula I-f where T is    CH₂-(3-(5-cyano-pyridin-2-yl)[1,2,4]oxadiazol-5-yl);-   Compound of Formula I-f where T is CH₂-(3-(5-dimethyl    amino-pyridin-2-yl) [1,2,4]oxadiazol-5-yl);-   Compound of Formula I-f where T is    CH₂-(3-(5-methoxy-pyridin-2-yl)[1,2,4]oxadiazol-5-yl);-   Compound of Formula I-f where T is    CH₂-(3-(5-fluoro-pyridin-2-yl)[1,2,4]oxadiazol-5-yl);-   Compound of Formula I-f where T is    CH₂-(3-(5-chloro-pyridin-2-yl)[1,2,4]oxadiazol-5-yl);-   Compound of Formula I-f where T is    CH₂-(3-(pyrimidin-5-yl)[1,2,4]oxadiazol-5-yl);-   Compound of Formula I-f where T is    CH₂-(5-(5-methyl-pyridin-2-yl)-[1,2,4]oxadiazol-3-yl);-   Compound of Formula I-f where T is    CH₂-(5-(5-cyclopropyl-pyridin-2-yl)-[1,2,4]oxadiazol-3-yl);-   Compound of Formula I-f where T is    CH₂-(5-(5-cyano-pyridin-2-yl)-[1,2,4]oxadiazol-3-yl);-   Compound of Formula I-f where T is CH₂-(5-(5-dimethyl    amino-pyridin-2-yl)-[1,2,4]oxadiazol-3-yl);-   Compound of Formula I-f where T is    CH₂-(5-(5-methoxy-pyridin-2-yl)-[1,2,4]oxadiazol-3-yl);-   Compound of Formula I-f where T is    CH₂-(5-(5-fluoro-pyridin-2-yl)-[1,2,4]oxadiazol-3-yl);-   Compound of Formula I-f where T is    CH₂-(5-(5-chloro-pyridin-2-yl)-[1,2,4]oxadiazol-3-yl);-   Compound of Formula I-f where T is    CH₂-(5-(pyrimidin-5-yl)-[1,2,4]oxadiazol-3-yl);-   Compound of Formula I-f where T is    CH₂-(5-(3-fluorophenyl)-isoxazol-3-yl);-   Compound of Formula I-f where T is    CH₂-(5-(3-chlorophenyl)-isoxazol-3-yl);-   Compound of Formula I-f where T is    CH₂-(5-(4-fluorophenyl)-isoxazol-3-yl);-   Compound of Formula I-f where T is CH₂-(5-(3-methoxy    phenyl)-isoxazol-3-yl);-   Compound of Formula I-f where T is CH₂-(5-phenyl)-isoxazol-3-yl);-   Compound of Formula I-f where T is CH₂-(5-methyl)-isoxazol-3-yl);-   Compound of Formula I-f where T is    CH₂-(5-(6-methoxy-pyridin-2-yl)-isoxazol-3-yl);-   Compound of Formula I-f where T is    CH₂-(5-(2-methoxy-pyridin-5-yl)-isoxazol-3-yl);-   Compound of Formula I-f where T is    CH₂-(5-(5-methyl-pyridin-2-yl)-isoxazol-3-yl);-   Compound of Formula I-f where T is    CH₂-(5-(5-cyclopropyl-pyridin-2-yl)-isoxazol-3-yl);-   Compound of Formula I-f where T is    CH₂-(5-(5-cyano-pyridin-2-yl)-isoxazol-3-yl);-   Compound of Formula I-f where T is CH₂-(5-(5-dimethyl    amino-pyridin-2-yl)-isoxazol-3-yl);-   Compound of Formula I-f where T is    CH₂-(5-(5-methoxy-pyridin-2-yl)-isoxazol-3-yl);-   Compound of Formula I-f where T is    CH₂-(5-(5-fluoro-pyridin-2-yl)-isoxazol-3-yl);-   Compound of Formula I-f where T is    CH₂-(5-(5-chloro-pyridin-2-yl)-isoxazol-3-yl);-   Compound of Formula I-f where T is    CH₂-(pyrimidin-5-yl)-isoxazol-3-yl);-   Compound of Formula I-f where T is    CH₂CH₂-(4-(pyridin-2-yl)-1H-imidazol-1-yl);-   Compound of Formula I-f where T is    CH₂CH₂-(4-(pyridin-3-yl)-1H-imidazol-1-yl);-   Compound of Formula I-f where T is    CH₂CH₂-(4-(6-methyl-pyridin-2-yl)-1H-imidazol-1-yl);-   Compound of Formula I-f where T is    CH₂CH₂-(4-(4-methoxy-pyridin-2-yl)-1H-imidazol-1-yl);-   Compound of Formula I-f where T is    CH₂-(4-(pyridin-2-yl)-pyrazol-4-yl);-   Compound of Formula I-f where T is    CH₂-(4-(pyridin-3-yl)-pyrazol-4-yl);-   Compound of Formula I-f where T is    CH₂-(4-(6-methyl-pyridin-2-yl)-pyrazol-4-yl);-   Compound of Formula I-f where T is    CH₂-(4-(4-methoxy-pyridin-2-yl)-pyrazol-4-yl);-   Compound of Formula I-f where T is    CH₂-(4-(5-methoxy-pyridin-2-yl)-pyrazol-4-yl);-   Compound of Formula I-f where T is    CH₂-(1-(pyridin-2-yl)-1H-imidazol-4-yl);-   Compound of Formula I-f where T is    CH₂-(1-(pyridin-3-yl)-1H-imidazol-4-yl);-   Compound of Formula I-f where T is    CH₂-(1-(6-methyl-pyridin-2-yl)-1H-imidazol-4-yl);-   Compound of Formula I-f where T is    CH₂-(1-(4-methoxy-pyridin-2-yl)-1H-imidazol-4-yl);-   Compound of Formula I-f where T is    CH₂-(1-(5-methoxy-pyridin-2-yl)-1H-imidazol-4-yl);-   Compound of Formula I-f where T is    CH₂-(2-(pyridin-2-yl)-oxazol-4-yl);-   Compound of Formula I-f where T is    CH₂-(2-(pyridin-3-yl)-oxazol-4-yl);-   Compound of Formula I-f where T is    CH₂-(2-(6-methyl-pyridin-2-yl)-oxazol-4-yl);-   Compound of Formula I-f where T is    CH₂-(2-(4-methoxy-pyridin-2-yl)-oxazol-4-yl);-   Compound of Formula I-f where T is    CH₂-(2-(5-methoxy-pyridin-2-yl)-oxazol-4-yl);

The compounds of present invention include stereoisomers. The term“stereoisomer” refers to compounds, which have identical chemicalcomposition, but differ with regard to arrangement of the atoms and thegroups in space. These include enantiomers, diastereomers, geometricalisomers, atropisomer and conformational isomers. Geometric isomers mayoccur when a compound contains a double bond or some other feature thatgives the molecule a certain amount of structural rigidity. Anenantiomer is a stereoisomer of a reference molecule that is thenonsuperimposable mirror image of the reference molecule. A diastereomeris a stereoisomer of a reference molecule that has a shape that is notthe mirror image of the reference molecule. An atropisomer is aconformation of a reference compound that converts to the referencecompound only slowly on the NMR or laboratory time scale. Conformationalisomers (or conformers or rotational isomers or rotamers) arestereoisomers produced by rotation about a bonds, and are often rapidlyinterconverting at room temperature. Racemic mixtures are alsoencompassed within the scope of this invention. Some of the compounds ofthe present invention may have trans and cis isomers and geometric E-and Z-isomers. The wavy bond indicates that the compounds may be presentas either of E- or Z-isomer. Also some of the compounds according tothis invention may exist as diastereomers. In addition, where theprocess for the preparation of the compounds according to the inventiongive rise to mixture of stereoisomers, these isomers, may be separatedby conventional techniques such as preparative chromatography and HPLC.The compounds may be prepared as a single stereoisomer or in racemicform as a mixture of some possible stereoisomer.

Furthermore, some of the compounds may exists as different polymorphssuch as crystalline or amorphous forms and as such are intended to beincluded in the present invention. In addition, some of the compoundsmay form solvates with water (i.e. hydrates) which, contains variousamounts of water, for instance the hydrate, hemihydrate andsesquihydrate forms. Also the compound can form solvates with commonorganic solvents, and such solvates are also intended to be encompassedwithin the scope of this invention.

DESCRIPTION OF TERMS

The following definitions are used, unless otherwise described.

The term “C₁-C₆ alkyl” refers to saturated, straight or branched chainhydrocarbon radicals containing between one and six carbon atoms.Examples of C₁-C₆ alkyl radicals, include but are not limited to,methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomerssuch as iso-propyl, iso-butyl, tert-butyl.

The term “C₂-C₆ alkenyl” refers to straight or branched-chainhydrocarbon radicals comprising two to six carbon atoms, which containone or more carbon-carbon double bonds. Examples of C₂-C₆ alkenylradicals, include but are not limited to, ethenyl, propenyl, butenyl,1-methyl-2-buten-1-yl, and the like.

The term “C₂-C₆ alkynyl” refers to straight or branched chainhydrocarbon radicals comprising two to six carbon atoms respectively,which contain one or more carbon-carbon triple bonds. Examples of C₂-C₆alkynyl radicals, include but are not limited to, ethynyl, propynyl,butynyl, 1-methyl-2-butyn-1-yl, and the like.

The substituted C₁-C₆ alkyl, substituted C₂-C₆ alkenyl, C₂-C₆substituted alkynyl is defined as the respective alkyl, alkenyl, alkynylsubstituted, by independent replacement of one or two or three of thehydrogen atoms thereon with Cl, Br, F, 1, NO₂, CN, OH, haloalkyl, C₁-C₆alkoxy, amino, alkylamino, dialkylamino, mercapto, formyl, carboxy,alkoxycarbonyl and carboxamide (C(O)NR′R″), aryl, heteroaryl,substituted aryl, substituted heteroaryl.

Examples of C₁-C₆ alkoxy are methoxy, ethoxy, propyloxy, isopropyloxy,butyloxy, pentyloxy, hexyloxy.

The term “haloalkyl” denotes an alkyl group, as defined above, havingone, two or three halogen atoms attached thereto and is exemplified bysuch groups as chloromethyl, bromoethyl, trifluoromethyl, and the like.

The term “alkylamino” refers to a group having the structure —NH(C₁-C₆alkyl) where C₁-C₆ alkyl is as previously defined.

The term “dialkylamino” refers to a group having the structure —N(C₁-C₆alkyl) (C₁-C₆ alkyl), where C₁-C₆ alkyl is as previously defined.Examples of dialkylamino are, but not limited to, dimethylamino,diethylamino, methylethylamino and the like.

The term “aryl” refers to a mono (6-membered) or bicyclic carbocyclicring system having one or two aromatic ring including but not limited tophenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.

The term “heteroaryl” refers to a mono i.e. 5-6 membered or bicyclici.e. fused aromatic ring system having at least one carbon atom of thearomatic ring replaced by an atom selected from the group of N, O, S.The ring may be connected to the remaining part of the molecule via anyof the ring atoms. For example pyridinyl, pyrazinyl, pyrimidinyl,pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, thiadiazolyl, oxadiazolyl, thienyl, triazolyl, triazinyl,tetrazolyl, furanyl, N-oxo-pyridinyl, and the like. It includes thefused biaryl systems such as indolyl, quinolinyl, isoquinolinyl,benzothiazolyl, benzoxazolyl, benzothienyl, N-oxo-quinolyl,benzimidazolyl, benzopyranyl, benzoisothiazolyl, benzodiazinyl,benzofurazanyl, indazolyl, indolizinyl, benzofuryl, quinoxalinyl,pyrrolopyridinyl, furopyridinyl (such as furo[2,3-c]pyridinyl,furo[3,2-b]pyridinyl, furo[2,3-b]pyridinyl), naphthyridinyl,phthalazinyl, pyridinopyridinyl, quinazolinyl, thienofuryl,thienopyridinyl, thienotheinyl, purinyl (such as 9H-purin-1-yl,6-amino-9H-purin-9-yl), pyridinyl-1H-pyrazol-1-yl and the like.

The aryl or the heteroaryl group can be optionally substituted byindependent replacement of one or more of hydrogen atoms thereon withsubstituents selected from C₁-C₆ alkyl, substituted C₁-C₆ alkyl, cyano,hydroxy, halogen, amino, formyl, carboxy, carboxamide, C₁-C₆ alkoxy,C₁-C₆ thioalkoxy, C₁-C₆ alkylcarbonyl, amino, alkylamino, dialkylamino,mercapto, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, alkylthio,arylthio, heteroarylthio, haloalkyl.

The “aralkyl” is defined as an alkyl group substituted with an arylgroup for example benzyl, benzhydryl, trityl, wherein the aryl group maybe optionally substituted as defined below.

The “heteroaralkyl” is defined as an alkyl group substituted with aheteroaryl group for example pyridinyl-methyl wherein the heteroarylgroup may be optionally substituted as defined below.

The “aroyl” group refers to a carbonyl group attached to an aryl groupfor example benzoyl, wherein the aryl group may be optionallysubstituted as defined below.

The “heteroaroyl” is defined as a carbonyl group attached to aheteroaryl group for example pyridinyl carbonyl, wherein the heteroarylgroup may be optionally substituted as defined below.

The “aralkanoyl” refers a carbonyl group attached to an aralkyl groupfor example phenylacetyl. The “heteroaralkanoyl” refers a carbonyl groupattached to heteroaralkyl group for example pyridinylylacetyl. Thecycloalkyl refers to 3-7 membered cyclic structures for examplecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.

The heterocyclyl refers to 3-7 membered cyclic structures including oneor more heteroatoms such as N, O, S or can be defined as up to 4heteroatoms selected from N, O, S. Examples of heterocyclyls areoxetanyl (oxetane is a four membered ring with an oxygen in the ringoxetanyl is a substituted oxetane). pyrrolidinyl, pyrazolinyl,imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, isoxazolinyl,thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, piperidinyl,piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl,4-oxo piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl,morpholinyl, [1,3]-dioxolane and the like.

The “hydroxyl protecting group” as used herein refers to an easilyremovable group which is known in the art to protect a hydroxyl groupagainst undesirable reaction during synthetic procedures and to beselectively removable. The use of hydroxy-protecting groups againstundesirable reactions during a synthesis procedure and any suchprotecting groups are known cf., for example, T. H. Greene and P. G. M.Wuts, Protective Groups in Organic Synthesis, 2^(nd) edition, John Wiley& sons, New York (1991). Examples of hydroxyl protecting groups includebut are not limited to triethylsilyl, trimethylsilyl, acetyl, benzoyl,methoxymethyl, methoxyethoxymethyl, benzyl, tertbutyldimethylsilyl andthe like.

The terms “halo”, “halide” and “halogen” as used herein refer to an atomselected from fluorine, chlorine, bromine and iodine. The term “formyl”as used herein refers to a group of Formula —CHO. The term “sulphonyl”refers to a group of Formula —SO₂—. “Thiol” or “mercapto” refers to thegroup —SH.

The term “C₁-C₆ alkoxy” refers to a C₁-C₆ alkyl group, as previouslydefined, attached to the parent molecular moiety through an oxygen atom.Examples of C₁-C₆-alkoxy include, but are not limited to, methoxy,ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy andn-hexoxy.

The term “carboxamide” as used herein refers to a group of FormulaC(O)NR′R″ wherein R′ and R″ are independently selected from hydrogen orC₁-C₆ alkyl or R′ and R″ taken together may form a six or five memberedheterocycle such as piperidine, pyrrolidine, piperazine and the like.

The term “ester” or “alkoxycarbonyl” refers to an C₁-C₆ alkoxy groupattached to the parent molecular moiety through a carbonyl group such asmethoxycarbonyl (CO₂Me), ethoxycarbonyl (CO₂Et), and the like.

The term “(C₁-C₆)alkylcarbonyl” unless otherwise indicated, includes—C(O)-alkyl groups wherein “alkyl” is as defined above.

The terms “Me”, “Et”, “Ph”, “allyl” stands for methyl, ethyl, phenyl andCH₂CH═CH₂ respectively. “MEM” stands for methoxyethoxymethyl.

The term “animal” refers to an animal such as a mammal, fish or a bird.

The phrase “pharmaceutically acceptable salt” as used herein refers toone or more salts of the free base of the invention which possess thedesired pharmacological activity of the free base and which are neitherbiologically nor otherwise undesirable. The salts are suitable for usein contact with the tissues of human and lower animals without unduetoxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein byreference. The salts can be prepared in situ during the final isolationand purification of the compounds of the invention, or separately byreacting the free base function with a suitable acid. These salts may beobtained from inorganic or organic acids. Examples of inorganic acidsare hydrochloric acid, nitric acid, perchloric acid, hydrobromic acid,sulphuric acid or phosphoric acid. Examples of organic acids are aceticacid, propionic acid, oxalic acid, glycolic acid, lactic acid, pyruvicacid, malonic acid, succinic acid, malic acid, maleic acid, fumaricacid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelicacid, methanesulphonic acid, p-toluene sulphonic acid, salicyclic acidand the like. Also included are the salts with various amino acids suchas alanine, arginine, asparagine, aspartic acid, cysteine, glutamine,glutamic acid, glycine, histidine, isoleucine, leucine, lysine,methionine, phenylalanine, proline, serine, threonine, tryptophan,tyrosine or valine or the optically active isomers thereof or theracemic mixtures thereof or dipeptides, tripeptides and polypeptidesderived from the monoaminoacid units thereof.

Other pharmaceutically acceptable salts include adipate, alginate,ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate,butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, glucoheptonate,glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate,hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate,lauryl sulfate, malonate, 2-naphthalenesulfonate, nicotinate, oleate,palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike.

Salt of an acid moiety in the compound can also be prepared by reactingwith a suitable base. These suitable salts are furthermore those of theinorganic or organic bases. Inorganic bases such as KOH, NaOH, Ca(OH)₂,Al(OH)₃. The organic base salts from basic amines such as ethylamine,triethylamine, diethanolamine, ethylenediamine, guanidine orheterocyclic amines such as piperidine, hydroxyethylpyrrolidine,hydroxyethylpiperidine, morpholine, piperazine, N-methyl piperazine andthe like or basic amino acids such as optically pure and racemic isomersof arginine, lysine, histidine, tryptophan and the like.

Further pharmaceutically acceptable salts include, when appropriate,nontoxic ammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, lower alkyl sulfonate and aryl sulfonate.

“Therapeutically effective amount” means that amount of activecompound(s) or pharmaceutical agent(s) that elicit the biological ormedicinal response in a tissue system, animal or human sought by aresearcher, veterinarian, medical doctor or other clinician, whichresponse includes alleviation of the symptoms of the disease or disorderbeing treated. The specific amount of active compound(s) orpharmaceutical agent(s) needed to elicit the biological or medicinalresponse will depend on a number of factors, including but not limitedto the disease or disorder being treated, the active compound(s) orpharmaceutical agent(s) being administered, the method ofadministration, and the condition of the patient. The term “treatment”unless otherwise indicated, includes the treatment or prevention of amicrobial infection as provided in the method of the present invention.

As used herein, unless otherwise indicated, the term “microbialinfection(s)” includes bacterial infections and protozoa infectionswhich occur in human or animals including mammals, fish and birds aswell as disorders related to bacterial infections and protozoainfections that may be treated or prevented by administering antibioticssuch as the compounds of the present invention. Such bacterialinfections and protozoa infections and disorders related to suchinfections include the following: pneumonia, otitis media, sinusitus,bronchitis, tonsillitis, and mastoiditis related to infection byStreptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis,Staphylococcus aureus, or Peptostreptococcus spp.; pharynigitis,rheumatic fever, and glomerulonephritis related to infection byStreptococcus pyogenes, Groups C and G streptococci, Clostridiumdiptheriae, or Actinobacillus haemolyticum; respiratory tract infectionsrelated to infection by Mycoplasma pneumoniae, Legionella pneumophila,Streptococcus pneumoniae, Haemophilus influenzae, or Chlamydiapneumoniae; uncomplicated skin and soft tissue infections, abscesses andosteomyelitis, and puerperal fever related to infection byStaphylococcus aureus, coagulase-positive staphylococci (i.e., S.epidermidis, S. hemolyticus, etc.), Streptococcus pyogenes,Streptococcus agalactiae, Streptococcal groups C-F (minute-colonystreptococci), viridans streptococci, Corynebacterium minutissimum,Clostridium spp., or Bartonella henselae; uncomplicated acute urinarytract infections related to infection by Staphylococcus saprophyticus orEnterococcus spp.; urethritis and cervicitis; and sexually transmitteddiseases related to infection by Chlamydia trachomatis, Haemophilusducreyi, Treponema pallidum, Ureaplasma urealyticum, or Neiserriagonorrheae; toxin diseases related to infection by S. aureus (foodpoisoning and Toxic shock syndrome), or Groups A, B, and C streptococci;ulcers related to infection by Helicobacter pylori; systemic febrilesyndromes related to infection by Borrelia recurrentis; Lyme diseaserelated to infection by Borrelia burgdorferi; conjunctivitis, keratitis,and dacrocystitis related to infection by Chlamydia trachomatis,Neisseria gonorrhoeae, S. aureus, S. pneumoniae, S. pyogenes, H.influenzae, or Listeria spp.; disseminated Mycobacterium avium complex(MAC) disease related to infection by Mycobacterium avium, orMycobacterium intracellulare; gastroenteritis related to infection byCampylobacter jejuni; intestinal protozoa related to infection byCryptosporidium spp.; odontogenic infection related to infection byviridans streptococci; persistent cough related to infection byBordetella pertussis; gas gangrene related to infection by Clostridiumperfringens or Bacteroides spp.; and atherosclerosis related toinfection by Helicobacter pylori or Chlamydia pneumoniae. Bacterialinfections and protozoa infections and disorders related to suchinfections that may be treated or prevented in animals include thefollowing: bovine respiratory diseases related to infection by P. haem.,P. multocida, Mycoplasma bovis, or Bordetella spp.; cow enteric diseaserelated to infection by E. coli or protozoa (i.e., coccidia,cryptosporidia, etc.); dairy cow mastitis related to infection by Staph.aureus, Strep. uberis, Strep. agalactiae, Strep. dysgalactiae,Klebsiella spp., Corynebacterium, or Enterococcus spp.; swinerespiratory disease related to infection by A. pleuro., P. multocida, orMycoplasma spp.; swine enteric disease related to infection by E. coli,Lawsonia intracellularis, Salmonella, or Serpulina hyodyisinteriae; cowfootrot related to infection by Fusobacterium spp.; cow metritis relatedto infection by E. coli; cow hairy warts related to infection byFusobacterium necrophorum or Bacteroides nodosus; cow pink-eye relatedto infection by Moraxella bovis; cow premature abortion related toinfection by protozoa (i.e. neosporium); urinary tract infection in dogsand cats related to infection by E. coli; skin and soft tissueinfections in dogs and cats related to infection by Staph. epidermidis,Staph. intermedius, coagulase neg. Staph. or P. multocida; and dental ormouth infections in dogs and cats related to infection by Alcaligenesspp., Bacteroides spp., Clostridium spp., Enterobacter spp.,Eubacterium, Peptostreptococcus, Porphyromonas, or Prevotella.

Antimicrobial Activity

Susceptibility tests can be used to quantitatively measure the in vitroactivity of an antimicrobial agent against a given bacterial isolate.Compounds were tested for in vitro antibacterial activity by amicro-dilution method. Minimal Inhibitory Concentration (MIC) wasdetermined in 96 well microtiter plates utilizing the appropriateMueller Hinton Broth medium for the observed bacterial isolates.Antimicrobial agents were serially diluted (2-fold) in DMSO to produce aconcentration range, from about 64 μg/ml to about 0.03 μg/ml. Thediluted compounds (2 μl/well) were then spotted to sterile 96-wellmicrotiter plates. The inoculum for each bacterial strain was adjustedto 5.5×10⁵ CFU/ml in appropriate MIC medium; 200 μl/well of thisinoculum was added to the 96-well microtiter plate resulting in a finalconcentration of 1×10⁵ CFU/ml. The 96 well plates were covered andincubated in a humidified atmosphere at 35±2° C. for 16-24 h dependingon the bacterial strain tested. Following incubation, plate wells werevisually examined by Optical Density measurement for the presence ofgrowth (turbidity). The lowest concentration of an antimicrobial agentat which no visible growth occurs was defined as the MIC. The compoundsof the invention generally demonstrated an MIC in the range from about64 μg/ml to about 0.03 μg/ml.

All in vitro testing follows the guidelines described in the ApprovedStandards M7-A5 protocol, published by the National Committee forClinical Laboratory Standards (NCCLS).

The present invention encompasses certain compounds, dosage forms, andmethods of administering the compounds to a human or other animalsubject. Specific compounds and compositions to be used in the inventionmust, accordingly, be pharmaceutically acceptable. As used herein, sucha “pharmaceutically acceptable” component is one that is suitable foruse with humans and/or animals without undue adverse side effects (suchas toxicity, irritation, and allergic response) commensurate with areasonable benefit/risk ratio.

The pharmaceutical compositions are prepared according to conventionalprocedures used by persons skilled in the art to make stable andeffective compositions. In the solid, liquid, parenteral and topicaldosage forms, an effective amount of the active compound or the activeingredient is any amount, which produces the desired results.

For the purpose of this invention the pharmaceutical compositions maycontain the active compounds of the invention, their derivatives, saltsand hydrates thereof, in a form to be administered alone, but generallyin a form to be administered in admixture with a pharmaceutical carrierselected with regard to the intended route of administration andstandard pharmaceutical practice. Suitable carriers which can be usedare, for example, diluents or excipients such as fillers, extenders,binders, emollients, wetting agents, disintegrates, surface activeagents and lubricants which are usually employed to prepare such drugsdepending on the type of dosage form.

Any suitable route of administration may be employed for providing thepatient with an effective dosage of the compound of the invention theirderivatives, salts and hydrates thereof. For example, oral, rectal,parenteral (subcutaneous, intramuscular, intravenous), transdermal,topical, ophthalmic, otic and like forms of administration may beemployed. Dosage forms include (solutions, suspensions, etc) tablets,pills, powders, troches, dispersions, suspensions, emulsions, solutions,capsules, injectable preparations, patches, ointments, creams, lotions,shampoos and the like.

The prophylactic or therapeutic dose of the compounds of the invention,their derivatives, salts or hydrates thereof, in the acute or chronicmanagement of disease will vary with the severity of condition to betreated, and the route of administration. In addition, the dose, andperhaps the dose frequency, will also vary according to the age, bodyweight and response of the individual patient. In general, the totaldaily dose range, for the compounds of the invention, the derivatives,salts or hydrates thereof, for the conditions described herein, is fromabout 200 mg to about 1500 mg, in single or divided doses. Whileintramuscular administration may be a single dose or up to 3 divideddoses, intravenous administration can include a continuous drip. It maybe necessary to use dosages outside these ranges in some cases as willbe apparent to those skilled in the art. The term “an amount sufficientto eradicate such infections but insufficient to cause undue sideeffects” is encompassed by the above-described dosage amount and dosefrequency schedule.

Pharmaceutical compositions of the present invention suitable for oraladministration may be presented as discrete units such as capsules,cachets, or tablets, or aerosol sprays, each containing a predeterminedamount of the active ingredient, as a powder or granules, or as asolution or a suspension in an aqueous liquid, a non-aqueous liquid, anoil-in-water emulsion, or a water-in-oil liquid emulsion. Suchcompositions may be prepared by any of the methods of pharmacy, but allmethods include the step of bringing into association the activeingredient with the carrier, which constitutes one or more necessaryingredients. In general, the compositions are prepared by uniformly andintimately admixing the active ingredient with liquid carriers or finelydivided solid carriers or both, and then, if necessary, shaping theproduct into the desired presentation.

The compositions of the present invention include compositions such assuspensions, solutions, elixirs, aerosols, and solid dosage forms.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit form, in which case solidpharmaceutical carriers are employed. Examples of suitable carriersinclude excipients such as lactose, white sugar, sodium chloride,glucose solution, urea, starch, calcium carbonate, kaolin, crystallinecellulose and silicic acid, binders such as water, ethanol, propanol,simple syrup, glucose, starch solution, gelatin solution, carboxymethylcellulose, shellac, methyl cellulose, potassium phosphate and polyvinylpyrrolidone, disintegrants such as dried starch, sodium alginate, agarpowder, laminaria powder, sodium hydrogen carbonate, calcium carbonate,Tween (fatty acid ester of polyoxyethylenesorbitan), sodium laurylsulfate, stearic acid monoglyceride, starch, and lactose, disintegrationinhibitors such as white sugar, stearic acid glyceryl ester, cacaobutter and hydrogenated oils, absorption promoters such as quaternaryammonium bases and sodium lauryl sulfate, humectants such as glyceroland starch, absorbents such as starch, lactose, kaolin, bentonite andcolloidal silicic acid, and lubricants such as purified talc, stearicacid salts, boric acid powder, polyethylene glycol and solidpolyethylene glycol.

The tablet, if desired, can be coated, and made into sugar-coatedtablets, gelatin-coated tablets, enteric-coated tablets, film-coatedtablets, or tablets comprising two or more layers.

If desired, tablets may be coated by standard aqueous or non-aqueoustechniques. In molding the pharmaceutical composition into pills, a widevariety of conventional carriers known in the art can be used. Examplesof suitable carriers are excipients such as glucose, lactose, starch,cacao butter, hardened vegetable oils, kaolin and talc, binders such asgum arabic powder, tragacanth powder, gelatin, and ethanol, anddisintegrants such as laminaria and agar.

In molding the pharmaceutical composition into a suppository form, awide variety of carriers known in the art can be used. Examples ofsuitable carriers include polyethylene glycol, cacao butter, higheralcohols, gelatin, and semi-synthetic glycerides.

In one embodiment method for treating or preventing microbial infectionsin a human or an animal, comprising administering to said animal orhuman a therapeutically effective amount of a compound of Formula I orthe pharmaceutical composition of compound of Formula I is provided. Themicrobial infections may be caused by Gram-positive, Gram-negativebacteria, aerobic, anaerobic bacteria, atypical bacteria or protozoa.

Abbreviations

Abbreviations which may be used in the descriptions of the schemes andthe examples that follow are: Ac for acetyl; AIBN forazobis-isobutyronitrile; Bn for benzyl; Boc for t-butoxycarbonyl; Bu₃SnHfor tributyltin hydride; Bz for benzoyl; CDI for carbonyldiimidazole;DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene; DBN for1,5-diazabicyclo[4.3.0]non-5-ene; DCC for 1,3-dicyclohexylcarbodiimide;DEAD for diethylazodicarboxylate; DIC for 1,3-diisopropylcarbodiimide;DMAP for dimethylaminopyridine; DMF for dimethyl formamide; DPPA fordiphenylphosphoryl azide; EtOAc for ethyl acetate; KHMDS for potassiumbis(trimethylsilyl)amide; LHMDS for Lithium bis(trimethylsilyl)amide;LDA for lithium diisopropyl amide; MeOH for methanol; Me₂S for dimethylsulfide; MOM for methoxymethyl; NaN(TMS)₂ for sodiumbis(trimethylsilyl)amide; NCS for N-chlorosuccinimide; NMO for4-methylmorpholine N-oxide; PCC for pyridinium chlorochromate; PDC forpyridinium dichromate; Ph for phenyl; TEA for triethylamine; THF fortetrahydrofuran; TPP or PPh₃ for triphenylphosphine; TBS for tert-butyldimethylsilyl; TMS for trimethylsilyl.

In a further embodiment is provided a process for the preparation ofmacrolide and ketolide compounds having Formula I, wherein the variableshave the previously defined meanings, the method comprising the processwill be better understood in connection with the following syntheticSchemes. The synthesis of the compounds of the invention can be broadlysummarized as

-   -   a. Synthesis of the novel macrolides bearing 11,12-γ-lactone    -   b. Synthesis of the novel ketolides    -   c. Further conversions to generate the compounds of Formula I.        a) Synthesis of the Novel Macrolides Bearing 11,12-γ-lactone

As depicted in the Scheme 1, erythromycin A or clarithromycin orderivatives of erythromycin and clarithromycin are used as the startingmaterial for the reactions. All the above starting materials are usedwith optionally protected hydroxyl and/or amino groups with a suitableprotecting group familiar to those skilled in the art. Exemplaryprotecting groups are, but not limited to silyl ethers such astriethylsilyl, trimethylsilyl, tert-butyldimethylsilyl,triisopropylsilyl. The protecting groups include benzyl, allyl, acetyl,benzoyl, pivalolyl and the like. For the amino protection,benzyloxycarbonyl, acetyl, tert-butoxycarbonyl (henceforth BOC) and thelike may be used. The suitable macrolide starting material, depicted bycompound (II) in the Scheme 1, is treated with triphosgene in a suitablesolvent such as halogenated solvents such as dichloromethane, chloroformor THF in the presence of pyridine to provide the 11,12-carbonate (III,wherein R1, R2, R2′ have the same meaning defined in Formula I).

The compound III obtained from Scheme 1, is dissolved in solvent such asethyl acetate, acetonitrile, tetrahydrofuran or mixtures thereof andtreated with a base such as 1,8-diazabicyclo[5.4.0]undec-7-ene, KHMDS,LDA, triethylamine at 50-80° C., to give compound IV.

The compound IV is treated with cyanoacetic acid in presence of a estercoupling reagent such as DCC, 2,4,6-trichlorobenzoyl chloride, EEDQ,EDCI, Boc-Cl in a presence of a base such as pyridine, DMAP,N,N-Diisopropylethylamine, triethylamine and the like in a suitablesolvent such as dichloromethane, acetonitrile, tetrahydrofuran,N,N-dimethylformamide or mixtures thereof to give compound Va. Thecompound Va is further treated with a base such as pyridine, DBU, DBN,LHMDS, LDA to give compound of Formula VI.

Alternatively, the compound IV, is dissolved in solvent such asdichloromethane or acetonitrile or tetrahydrofuran orN,N-dimethylformamide or mixtures thereof and treated with chloroaceticanhydride in presence of a base such as pyridine and dimethylaminopyridine at 5-40° C., to give compound Vb. The compound Vb, is dissolvedin a solvent such as acetonitrile or tetrahydrofuran orN,N-dimethylformamide or DMSO or mixture thereof and treated withpotassium cyanide at 15-40° C., to give compound VI.

The compound VI is dissolved in solvent such as tetrahydrofuran ormethanol or ethanol or mixture thereof and treated with hydroxylaminehydrochloride in the presence of base such as sodium bicarbonate orsodium acetate or potassium hydroxide to give compound VII (Scheme 2).

b) Synthesis of the Ketolide Derivatives:

For the synthesis of the C-3 ketolide, the cladinose sugar is removed byhydrolysis according to procedures described in the art.

The 3-O-cladinose sugar of the compound of Formula I-a is cleaved withan inorganic acid such as hydrochloric acid, sulphuric acid attemperature ranging from −10° C. to 60° C. for 0.5 to 24 h. to givecompound VIII as shown in Scheme 3. Before derivatizing the generatedC-3-hydroxyl, the 2′-OH group of the 5-desosamine is protected as shownin Scheme 3 by use of an acetyl group. The acetylation is done usingacetyl chloride or acetic anhydride in presence or absence of a base ina suitable solvent such as acetone, acetonitrile or dichoromethane, atroom temperature for 6-24 h to give compound (IX, R₂═COCH₃), Scheme 3.An alternate protecting group may also be used by treatment the compoundVIII with reagents such as trialkylsilyl chloride benzoyl chloride,benzoic anhydride, benzyl chloroformate, hexamethyldisilazane.

The conversion of the 3-hydroxy group to 3-ketone is accomplished byusing a Corey-Kim oxidation with N-chlorosuccinimide-dimethyl sulphide(NCS-DMS) or a Moffat oxidation with carbodiimide-dimethylsulphoxide(DMSO) complex in the presence of pyridinium trifluoroacetate orDess-Martin periodinane. Such name reactions are carried out accordingto general procedures described in the art. In general, the compound(IX, R₂═COCH₃ or R₂=TES), obtained in Scheme 3 is dissolved in achlorinated solvent such as dichloromethane or chloroform andDess-Martin periodinane reagent was added and stirred at an ambienttemperature for about 0.5 to 1 h to get the corresponding 3-ketonecompound X, Scheme 3.

c) Further Manipulations to Generate the Compounds of Formula I.

The manner in which the following procedures are to be used to providethe actual compounds listed in the table will be readily apparent tothose persons skilled in the art of synthesis. The sequence of thereactions can be altered as will be readily apparent to those personsskilled in the art of synthesis. The examples described in theExperimental section later in this specification are illustrative andrepresentative of how these procedures are to be used for all of thecompounds listed in the table.

For the O-acylation of the amidoxime in the 11,12-γ-lactone ring i.e.the formation of compound XIIa or XIIb, the unsubstituted amidoxime isesterified with a suitable carboxylic acid reagent of the FormulaR₉—COOH, wherein R₉ represents —(CH₂)_(m)—R₅, —(CH₂)_(m)—CH═CH—R₅,—(CH₂)_(m)—C≡C—R₅, —(CH₂)_(m)—B—R₅, —(CH₂)_(m)—CH═CH—B—R₅,—(CH₂)_(m)—C≡C—B—R₅, —(CH₂)_(m)—X—R₆, —(CH₂)_(m)—CH═CH—X—R₆,—(CH₂)_(m)—C≡C—X—R₆, wherein R₅, R₆, X, B and m are as defined above. Amixture of suitably substituted acid, a condensing agent such as EDC,EDCI, DCC or EEDQ, HBTU and 1-hydroxy-benzotriazole in a halogenatedsolvent such as chloroform or dichloromethane, acetonitrile, THF, DMFwas stirred at a temperature between −10° C. to 45° C. Compound ofFormula VIIa or VIIb was treated with the above mixture in the presenceof a such as catalyst N,N-dimethylamino pyridine, at the temperature inthe range of 0 to 45° C. to give compound of Formula XIa and XIbrespectively (Scheme 4).

The macrolide compounds of Formula XIIa are obtained from thecorresponding macrolides of Formula XIa by treating with a fluoridesource such as tetrabutylammonium fluoride or HF-pyridine complex,preferably HF-pyridine complex in a suitable solvent such asdichloromethane or chloroform or acetonitrile or DMF, at a temperaturein the range of 0° C. to 50° C.

For the ketolide compounds of Formula XIIb, the corresponding 3-hydroxylcompounds of Formula XIb are treated with an oxidizing agent asdescribed above for the ketolides in Scheme 3, followed by deprotectionof the 2′-hydroxyl of the desosamine sugar with a fluoride source asdescribed above to afford ketolides of Formula XIIb, wherein all thevariables are as defined above in Formula I.

The unsubstituted amidoxime was treated with a suitable isocyanate toobtain carbamates of Formula XVa or XVb as shown in Scheme 5.

Compound of Formula VIIa or VIIb was treated with isocyanate of FormulaR₉—N═C═O, wherein R₉ represents —(CH₂)_(m)—R₅, —(CH₂)_(m)—CH═CH—R₅,—(CH₂)_(m)—C≡C—R₅, —(CH₂)_(m)—B—R₅, —(CH₂)_(m)—CH═CH—B—R₅,—(CH₂)_(m)—C≡C—B—R₅, —(CH₂)_(m)—X—R₆, —(CH₂)_(m)—CH═C H—X—R₆,—(CH₂)_(m)—C≡C—X—R₆, wherein R₅, R₆, X, B and m are as defined above, ina solvent such as chloroform or dichloromethane, at a temperaturebetween 0 to 40° C., to afford the corresponding compound of FormulaXIVa and XIVb respectively.

The macrolide compounds of Formula XVa are obtained from thecorresponding macrolides of Formula XIVa by treating with a fluoridesource such as tetrabutylammonium fluoride or HF-pyridine complex,preferably HF-pyridine complex in a suitable solvent such asdichloromethane or chloroform or acetonitrile or DMF, at a temperaturein the range of 0° C. to 50° C.

For the ketolide compounds of Formula XVb, the corresponding 3-hydroxylcompounds of Formula XIVb are treated with a oxidizing agent asdescribed above for the ketolides in Scheme 3, followed by deprotectionof the 2′-hydroxyl of the desosamine sugar with a fluoride source asdescribed above to afford ketolides of Formula XIVb, wherein all thevariables are as defined above in Formula I.

For the O-alkylation of the amidoxime in the 11,12-γ-lactone ring i.e.the formation of macrolide or ketolide of Formula XVIIa or XVIIb asshown in Scheme 6, the compound of Formula VIIa or VIIb was treated witha suitable alkylating reagent of Formula halo-R₉ wherein R₉ represents—(CH₂)_(m)—R₅, —(CH₂)_(m)—CH═CH—R₅, —(CH₂)_(m)—C≡C—R₅—(CH₂)_(m)—B—R₅,—(CH₂)_(m)—CH═CH—B—R₅, —(CH₂)_(m)—C≡C—B—R₅, —(CH₂)_(m)—X—R₆,—(CH₂)_(m)—CH═CH—X—R₆, —(CH₂)_(m)—C≡C—X—R₆, wherein B, X, R₅, R₆ and mare as defined above and halo is a chlorine, bromine or iodine. Thecompound VIIa or VIIb was dissolved in a solvent such as benzene ortoluene or xylene or dialkyl ether or DMF or THF or mixture thereof, ata temperature in the range of 0-100° C., in the presence of a base suchas sodium hydride, potassium hydride or potassium carbonate or potassiumhydroxide, optionally in the presence of phase transfer catalyst such as18-crown-6-ether or trialkyl ammonium sulfate, to provide the compoundXVIa and XVIb. The macrolide compounds of Formula XVIIa are obtainedfrom the corresponding macrolides of Formula XVIa by treating with afluoride source such as tetrabutylammonium fluoride or HF-pyridinecomplex, preferably HF-pyridine complex in a suitable solvent such asdichloromethane or chloroform or acetonitrile or DMF, at a temperaturein the range of 0° C. to 50° C.

For the ketolide compounds of Formula XVIIb, the corresponding3-hydroxyl compounds of Formula XVIb are treated with a oxidizing agentas described above for the ketolides in Scheme 3, followed bydeprotection of the 2′-hydroxyl of the desosamine sugar with a fluoridesource as described above to afford ketolides of Formula XVIIb, whereinall the variables are as defined above in Formula I.

Compounds of Formula XXa or XXb are prepared as shown in Scheme 7 byusing Heck coupling reaction. Compound of Formula XVIIIa or XVIIIb, aretreated a halo-aryl reagent of Formula halo-R₅ or halo-X—R₆ in presenceof a palladium (II) or palladium (0) catalyst such as palladium acetate(Pd(OAc)₂) in presence of a phosphine reagent such astriphenylphosphine, tri(o-totyl)phosphine and a base such astriethylamine, sodium carbonate, sodium bicarbonate, or in presence ofsodium acetate, in a suitable solvent such as N,N-dimethylformamide(DMF), acetonitrile, tetrahydrofuran (THF) to give the correspondingcompound of Formula XIXa or XIXb respectively as shown in Scheme 7,wherein G is —(CH₂)_(m)—, -A-(CH₂)_(m)—; U is —R₅ or —X—R₆,

The macrolide compounds of Formula XXa are obtained from thecorresponding macrolides of Formula XIXa by treating with a fluoridesource such as tetrabutylammonium fluoride or HF-pyridine complex,preferably HF-pyridine complex in a suitable solvent such asdichloromethane, chloroform, acetonitrile, DMF or mixtures thereof, at atemperature in the range of 0° C. to 50° C.

For the ketolide compounds of Formula XXb, the corresponding 3-hydroxylcompounds of Formula XIXb are treated with an oxidizing agent asdescribed above for the ketolides in Scheme 3, followed by deprotectionof the 2′-hydroxyl of the desosamine sugar with a fluoride source asdescribed above to afford ketolides of Formula XXb, wherein all thevariables are as defined above in Formula I.

Compounds of Formula XXIIIa or XXIIIb are prepared as shown in Scheme 8by using Sonagashira coupling reaction. Compound of Formula XXIa or XXIbare treated a halo-aryl reagent of Formula halo-R₅ or halo-X—R₆, whereinR₅, R₆ are as defined above, in presence of a palladium catalyst such asdichlorobis(triphenylphosphine)palladium (II) or Pd(PPh₃)₄ in presenceof a base such as triethylamine, diethyl amine, butylamine, piperidine,in a suitable solvent such as N,N-dimethylformamide (DMF), acetonitrile,tetrahydrofuran (THF) to give the compound of Formula XXIIa or XXIIbrespectively as shown in Scheme 8.

The macrolide compounds of Formula XXIIIa are obtained from thecorresponding macrolides of Formula XXIIa by treating with a fluoridesource such as tetrabutylammonium fluoride or HF-pyridine complex,preferably HF-pyridine complex in a suitable solvent such asdichloromethane or chloroform or acetonitrile or DMF, at a temperaturein the range of 0° C. to 50° C.

For the ketolide compounds of Formula XXIIIb, the corresponding3-hydroxyl compounds of Formula XXIIb are treated with an oxidizingagent as described above for the ketolides in Scheme 3, followed bydeprotection of the 2′-hydroxyl of the desosamine sugar with a fluoridesource as described above to afford ketolides of Formula XXIIIb, whereinall the variables are as defined above in Formula I.

The macrolide or ketolide of Formula XXIVa or XXIVb, wherein T is—(CH₂)_(m)—CH═CH—R₅, —(CH₂)_(m)—C≡C—R₅, -A-(CH₂)_(m)—CH═CH—R₅,-A-(CH₂)_(m)—C≡C—R₅, —(CH₂)_(m)—CH═CH—X—R₆, —(CH₂)_(m)—C≡C—X—R₆,-A-(CH₂)_(m)—CH═CH—X—R₆, -A-(CH₂)_(m)—C≡C—X—R₆,

are treated with a hydrogenating catalyst such as 10% Pd/C, 5% Pd/C or20% Pd(OH)₂ in presence of a hydrogen source such as hydrogen gas,ammonium formate, to give the corresponding compounds saturatedcompounds.

Compound of Formula VIa or VIb is treated with a suitable reagent suchas azidotrimethylsilane, sodiumazide in presence of catalyst such astributyltinoxide to afford the corresponding tetrazol compound ofFormula XXVa or XXVb. The tetrazol may be further alkylated usingsuitable alkylating reagent of Formula R₃-halo to afford thecorresponding alkylated tetrazole derivatives, wherein R₃ is as definedabove.

Compound of Formula VIa or VIb is treated with a suitable diamine suchas ethylenediamine or propylenediamine in presence of sulphur at atemperature in the range of 100-150° C. to afford the correspondingdihydro imidazolyl compound of Formula XXVa or XXVb.

Compound of Formula VIIa or VIIb is treated with N,N-dimethylformamidedimethylacetal or trifluoroacetic anhydride, optionally in presence of abase such as triethylamine to afford the corresponding[1,2,4]-oxadiazole derivatives of Formula XXVa or XXVb.

The macrolide compounds of Formula XXVIa are obtained from thecorresponding macrolides of Formula XXVa by treating with a fluoridesource such as tetrabutylammonium fluoride or HF-pyridine complex,preferably HF-pyridine complex in a suitable solvent such asdichloromethane or chloroform or acetonitrile or DMF, at a temperaturein the range of 0° C. to 50° C.

For the ketolide compounds of Formula XXVIb, the corresponding3-hydroxyl compounds of Formula XXVb are treated with an oxidizing agentas described above for the ketolides in Scheme 9, followed bydeprotection of the 2′-hydroxyl of the desosamine sugar with a fluoridesource as described above to afford ketolides of Formula XXVIb, whereinall the variables are as defined above in Formula I.

Biological Activity

The compounds of this invention are useful antimicrobial agents,effective against various human and veterinary pathogens, includingmultiple-resistant staphylococci and streptococci, enteroccoci, as wellas anaerobic organisms such bacteroides and clostridia species, and acidresistant organisms such as Mycobacterium tuberculosis and Mycobacteriumavium.

Test Example 1

MIC Test Method: Overnight grown cultures of S. aureus organisms inTryptic Soya broth were diluted in Mueller Hinton Broth to give opticaldensity matching with MacFarland tube 0.5 standard. Cultures werefurther diluted 1:10 in Mueller Hinton broth. Using Denley's mutipointinoculator, 10⁴ cells were deposited on Mueller Hinton agar (Difco)containing range of 2 fold dilutions of test compounds. These plateswere incubated for 24 hrs at 35° C. and MIC results recorded. MIC isdefined as minimum drug concentration that inhibits test organisms. Fordetermining MIC of test compounds against Streptococcus pneumoniae,Mueller Hinton agar containing 5% sheep blood was employed. Thefollowing strains were used to screen the compounds of invention. Thecompounds inhibited the growth of these bacteria with MIC's in the rangeof about 0.03 μg/mL to about 64 μg/mL.

Strain Staphylococcus aureus ATCC 25923 Staphylococcus aureus 014Staphylococcus epidermidis 110 Staphylococcus haemolyticus ATCC 25923Enterococcus faecalis 401 Enterococcus faecium 303 Streptococcuspneumoniae 49619 Streptococcus pneumoniae 706 Streptococcus pyogenes 801Streptococcus pyogenes 805 Haemophilus influenzae 49247 Mycobacteriumtuberculosis Mycobacterium avium

The compounds and processes of the present invention will be betterunderstood in connection with the following examples, which are intendedas an illustration only and not limiting of the scope of the invention.Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art and such changes and modificationsincluding, without limitation, those relating to the chemicalstructures, substituents, derivatives, Formulations and/or methods ofthe invention may be made.

EXAMPLES

The following examples describe in detail the chemical synthesis of someof the representative compounds of the present invention. The proceduresare illustrations, and the invention should not be construed as beinglimited by chemical reactions and conditions they express. No attempthas been made to optimize the yields obtained in these reactions, and itwould be obvious to one skilled in the art that variations in reactiontimes, temperatures, solvents, and/or reagents could increase theyields.

Example 1 Compound III of Scheme 1, R₁ is CH₃, R₂, R_(2′) isTriethylsilyl

Step A: To a stirred solution of 6-methyl erythromycin A (15 g, 20.1mmol) in anhydrous acetonitrile (120 ml) cooled to 0° C. Triethyl amine(19.5 ml, 140 mmol), DMAP (12.25 g, 100 mmol) and chloro triethyl silane(20 ml, 120 mmol) were added under nitrogen atmosphere. The resultingmixture was stirred at 25-30° C. temperature for 3 hr. Then water (120ml) was added, the solid precipitated was filtered under suction. Thewet cake was stirred with methanol (50 ml) at 25-30° C. temperature for1 hr and filtered under suction, dried to provide step-1 product2′,4″-Di-TES-6-O-methyl-erythromycin A as white solid in 80% (16 g)yield. MS: m/z: 976.8 (M+1).

Step B: To a solution of product obtained in above step (10 g, 10.2mmol) in anhydrous dichloromethane (70 ml) was added pyridine (5 ml,61.2 mmol) and followed by triphosgene (3.04 g, 10.2 mmol) at 0° C.under an inert atmosphere. The reaction mixture was further stirred at0-5° C. for 0.5 h. To the reaction mixture water (15 ml) was added, theorganic layer was separated. The organic layer was dried (Na₂SO₄) andevaporated under reduced pressure to give the title compound (9.7 g) aswhite solid. m\z ([MH]⁺)=1002.5.

Example 2 Compound IV of Scheme 1, R₁ is CH₃, R₂, R_(2′) isTriethylsilyl

To a solution of Example 1 (9.5 g, 9.5 mmol) in ethyl acetate (70 ml),1,8-diazabicyclo[5.4.0]undec-7-ene (3 ml, 20 mmol) was added at anambient temperature and the reaction mixture was further heated underreflux for 6 h. The reaction mixture was cooled to room temperature andwater (15 ml) was added to it and stirred for 10 min. The organic layerwas separated, dried and evaporated under reduced pressure to afford thetitle compound (9.3 g). m\z ([MH]⁺)=958.

Example 3 Compound Vb of Scheme 1, R₁ is CH₃, R₂, R_(2′) isTriethylsilyl

To the solution of Example 2 (9.3 g, 9.7 mmol) in anhydrousdichloromethane (30 ml) was added pyridine (4.7 ml, 58.2 mmol), DMAP(0.6 g, 4.8 mmol) and followed by chloroacetic anhydride (3.7 g, 21.3mmol) at 0° C. After completion of addition it was allowed to come toroom temperature and stirred further for 3 h. To the reaction mixturewater (30 ml) was added and stirred vigorously for 10 min. and separatedthe organic layer. The organic layer was then washed with a saturatedsolution of sodium bicarbonate followed by the brine. The organic layerwas dried (Na₂SO₄) and upon removal of the solvent under reducedpressure a gummy mass was obtained which was taken into the methanol andstirred for 2 h to provide the title compound (8 g). m\z ([MH]⁺)=1034.

Example 4 Compound VI of Scheme 1, R₁ is CH₃, R₂, R_(2′) isTriethylsilyl

Method 1:

Example 3 (6 g, 5.8 mmol) was dissolved into N,N-dimethylformamide (20ml) and to it potassium cyanide (0.6 g, 8.7 mmol) was added carefullyunder inert atmosphere at room temperature. The reaction mixture wasfurther stirred for 2 h. The reaction mixture was filtered and pouredinto the 5% sodium bicarbonate solution (30 ml), the cream color solidseparated out was filtered and washed successively by solution offerrous sulphate and water. The crude solid obtained was crystallizedfrom dichloromethane and n-hexane to provide the title compound (5.15g). m\z ([MH]⁺)=1025.

Method 2:

Step A: Compound Va of Scheme 1, R₁ is CH₃, R₂, R₂ is triethylsilyl: Tothe stirred solution of cyanoacetic acid (1.11 g, 13.1 mmol) inanhydrous dichloromethane (50 ml), 2,4,6-trichlorobenzoyl chloride wasadded at 0° C. N,N-Diisopropylethylamine (2.05 ml, 13.1 mmol) was addedto the reaction mixture and it was stirred at 0° C. for 30 min. Example2 (5 gm, 5.3 mmol) and N,N-diisopropylethylamine (2.05 ml, 13.1 mmol)were added to the reaction mixture and it was stirred at 25-30° C.temperature for 24 hr. To the reaction mixture was quenched by additionof aqueous solution of saturated sodium bicarbonate (50 ml) and stirredvigorously for 10 min. Organic layer was separated. The organic layerwas washed with a water (50 ml), dried over Na₂SO₄ and solvent wasevaporated under vacuum to afford yellow foam. The foam was stirred withacetonitrile at 0-5° C. and filtered to give step-4 product as a paleyellow solid in 70% (3.7 gm) yield. MS: m\z: 1025.7 (M+1).

Step B: To the stirred solution of product obtained in above step (3.6g, 3.51 mmol) in N,N-dimethylformamide (15 ml),1,8-diazabicyclo[5.4.0]undec-7-ene (0.545 g. 3.51 mmol) added at 25-30°C. temperature and stirred for 1 hr. Reaction mixture was diluted withwater (50 ml) and the solid was filtered under suction to afford titlecompound in 40% (1.5 g) yield. MS: m\z: 1025.7 (M+1).

Example 5 Compound VII of Scheme 2, R₁ is CH₃, R₂, R_(2′) isTriethylsilyl, Y′ is H, Y is O-cladinose

To a solution of Example 4 (5 g, 4.8 mmol) in methanol (25 ml),hydroxylamine hydrochloride (3.7 g, 53.7 mmol) and sodium bicarbonate(4.6 g, 54.6 mmol) was added and heated under reflux for 15 h. The solidseparated out was filtered and washed with water. The crude solidobtained was purified by recrystallization from methanol to afford thetitle compound as white solid (4.3 g). m\z ([MH]⁺)=1058.

Example 6 Compound IX of Scheme 3, R₁ is CH₃, R₂ is Triethylsilyl, Q isCN

To a solution of Example 4 (10 g, 9.7 mmol) in acetonitrile (40 ml), a2N HCl (10 ml) was slowly added at 0° C. The reaction mixture wasfurther stirred at room temperature for 4 h. It was then cooled to 0° C.and the pH of the solution was brought to 8 by slow addition of asaturated solution of sodium bicarbonate. The aqueous layer wasextracted into chloroform (3×25 ml). The combined organic layer wasdried (Na₂SO₄) and evaporated under reduced pressure to furnish thecrude solid. The solid obtained was purified by column chromatographyover silica gel using chloroform:methanol (7:3) as an eluent to providea white solid (6 g). In this reaction condition the hydroxyl protectinggroup of desosamine sugar was cleaved, therefore we have again protectedthe hydroxyl group by using the following procedure. The deprotectedsolid (6 g, 9.4 mmol) was taken into acetonitrile:N,N-dimethylformamide(8:2, 30 ml). To this solution triethylamine (5.2 ml, 37.6 mmol), DMAP(4.5 g, 37.6 mmol) followed by chlorotriethylsilane (6.3 ml, 37.6 mmol)was added at room temperature and stirred for 3 h. To the reactionmixture water (50 ml) was added and it was extracted into n-hexane (3×40ml). The combined organic layer was dried (Na₂SO₄) and evaporated togive the gummy mass, which on trituration with n-pentane provided thetitle compound as a white solid (6 g). m\z ([MH]⁺)=753.

Example 7 Compound VII of Scheme 2, R₁ is CH₃, R₂ is Triethylsilyl, Y isOH, Y′ is H

Using the Example 6 (0.5 g) and following the same procedure asdescribed for the Example 5, the title compound obtained a white solid(0.5 g). m\z ([MH]⁺)=786.

Example 8 Compound X of Scheme 3, R₁ is CH₃, R₂ is Triethylsilyl, Q isCN

The Example 6 (6 g, 7.9 mmol) was dissolved in dichloromethane (60 ml).To the reaction mixture a solution Dess-Martin periodinane (15% in DCM,27 ml, 9.5 mmol) was added under an inert atmosphere. The reactionmixture was stirred at room temperature for 5 min. and a solution ofNa₂S₂O₃ (10% in saturated aqueous solution of sodium bicarbonate, 60 ml)was added and stirred for 10 min. The organic layer was separated andthe aqueous layer was extracted with dichloromethane (3×15 ml) and thecombine organic layer was dried (Na₂SO₄). The removal of the solventunder reduced pressure provided the crude solid, which was purified bycolumn chromatography over silica gel using n-hexane:EtOAc (8:2) as aneluent. The title compound was obtained a white solid (3.5 g). m\z([MH]⁺)=751.

Example 9 Compound VII of Scheme 2, R₁ is CH₃, R₂ is Triethylsilyl, Y,Y′ Together C═O

Using the Example 8 (3.5 g, 4.6 mmol) and following the same procedureas described for the Example 5, the title compound obtained a whitesolid (3.5 g). m\z ([MH]⁺)=784.

Example-10 Compound of Formula I-c, R₁ is CH₃, T is H

To the solution of Example 5 (0.950 g, 0.89 mmol) in anhydrous THF (25ml) was added 70% hydrogen fluoride in pyridine (77 μl, 2.7 mmol). Thereaction mixture was stirred at an ambient temperature under inertatmosphere for 14 h. To the reaction mixture water (15 ml) was added andextracted with ethyl acetate (3×15 ml). The combined organic layer wasdried (Na₂SO₄) and evaporated under reduced pressure. The thick liquidon trituration with n-pentane furnished the title compound (0.582 g) asa white solid. MS 830 (M+H)⁺.

Example-11 Compound of Formula I-b where Het is 1H-tetrazol-5-yl

Step A: To the stirring solution of Example 4 (29.3 mmol) in toluene wasadded tributyltinoxide (0.25 eq) and azidotrimethylsilane (2 eq). Thereaction mixture was heated at 90° C. for 16-20 hours. The reactionmixture was concentrated and purified using silica gel columnchromatography (Ethyl acetate:Hexane 1:1). Yield 70%.

Step C: To the stirring solution of compound obtained in Step B (0.36mmol) in tetrahydrofuran was added HF-Pyridine complex (3.5 eq) andstirred it for 16 hours. The reaction mixture was concentrated and waterwas added. The product was extracted in chloroform. Yield 80%. Yield:Mass: m/z: 840.1 (M+H)⁺, M. P. 162-164° C.

Example-12 Compound of Formula I-b where Het is2-(1-methoxy-ethoxymethyl)-1H-tetrazol-5-yl Example-13 Compound ofFormula I-b where Het is 2-(2-methoxy-ethoxymethyl)-2H-tetrazol-5-yl

Step A: To the stirring solution of Example 4 (29.3 mmol) in toluene wasadded tributyltinoxide (0.25 eq) and azidotrimethylsilane (2 eq). Thereaction mixture was heated at 90° C. for 16-20 hours. The reactionmixture was concentrated and purified using silica gel columnchromatography (Ethyl acetate:Hexane 1:1). Yield 70%.

Step B: To the stirring solution of the compound obtained in above stepA (0.93 mmol) in acetone was added TEA (1.3 eq) and MEM-Cl (1.2 eq) andheated it at reflux temperature for 1 hours. The reaction mixture wasconcentrated and water was added. Filtered the solid residue and driedit over high vacuo. It was a mixture of two regio isomers. It was thenseparated using 100-200-mesh silica gel column chromatography. Yield42%.

Step C: To the stirring solution of compound obtained in Step B (0.36mmol) in tetrahydrofuran was added HF-Pyridine complex (3.5 eq) andstirred it for 16 hours. The reaction mixture was concentrated and waterwas added. The product was extracted in chloroform. Yield 80%. Yield:Isomer-A: Mass: m/z: 928 (M+H). M.P. 210-212° C., Isomer-B: 190 mg Mass:m/z: 928 (M+H)⁺, M. P. 150-152° C.

Following examples were prepared by using above procedure and by usingreactant A.

Formula I-b

Mp Mass Example Het Reactant (A) (° C.) (M + 1) 14

Tetrazol-2-yl-acetic acid ethyl ester 150-154 926.11 15

2-Tetrazol-2-yl- acetamide 198-200 897.1 16

Tetrazol-2-yl- acetonitrile 218-220 879.1 17

Tetrazol-1-yl- acetonitrile 202-204 879.1 18

2-Allyl-2H-tetrazole 188-190 880.1 19

Tetrazole-2- carboxylic acid (3- fluoro-phenyl)- methyl amide 230-2321005.1 20

2-Tetrazole-2-yl- ethanol 220-222 884.1

Example-21 Compound of Formula I-c, T is CO(CH₂)₂-(pyridin-3-yl), R₁ isCH₃

To the solution of 3-pyridin-3-yl-propionic acid (1.42 g, 7.5 mmol) indichloromethane (40 ml) was added dicyclohexyl carbodiimide (1.55 g, 7.5mmol) and stirred for 0.5 h at room temperature. To this reactionmixture Example 5 (2 g, 1.9 mmol) followed by dimethyl amino pyridine(0.131 g, 1.0 mmol) was added and stirred further for 2 h. The solidprecipitated out was filtered and washed with dichloromethane (10 ml).The combined filtrate was evaporated under reduced pressure to furnish athick liquid, which was used as it is without purification for furtherreaction.

To the solution of thick liquid (1.8 g, 1.5 mmol) obtained as above inTHF (10 ml) was added 70% hydrogen fluoride in pyridine (130 μl, 4.53mmol) under inert atmosphere and stirred for 15 h. The residue obtainedafter evaporation of solvent under reduced pressure was dissolved inethyl acetate (15 ml) and washed with water (2×10 ml). The organic layerwas dried (Na₂SO₄) and evaporated under reduced pressure to provide awhite solid as title compound (1.3 g, 82%). MS 963 (M+H)⁺.

Using the above procedure following examples were synthesized by usingthe corresponding carboxylic acid.

MP Mass Example T Reactant (A) (° C.) (M + 1) 22 COCH₂O-(2-chlorophenyl)(2-Chloro-phenoxy)-acetic 150-152 998 acid 23 CO(CH₂)₂-(4-dimethyl3-(4-dimethylamino-phenyl)- 168-170 996 amino)phenyl propionic acid 24CO(CH₂)₂-(3-fluoro)phenyl 3-(3-fluorophenyl)-propionic 170-172 980 acid25 CO(CH₂)₂-(4-(4-methyl- 3-[4-(4-methyl-piperazin-1- 168-170 1060piperazine)phenyl) yl)-phenyl]-propionic acid 26 CO(CH₂)₂-(4-(4-acetyl-3-[4-(4-acetyl-[1,2,3]triazol-1- 174-176 1071[1,2,3]triazol-1-yl))-phenyl yl)-phenyl]-propionic acid 27CO(CH₂)₂-(4-phenyl- 3-(4-phenyl-piperazin-1-yl)- 165-167 1045piperazinyl) propionic acid 28 CO(CH₂)₂-(4-(2-methoxy-3-[4-(2-methoxy-phenyl)- 155-156 1076 phenyl)-piperazine-1-yl)piperazin-1-yl]-propionic acid 29 COCH₂—S-(3-methoxy(3-methoxy-phenylsulfanyl)- 158-160 1010 phenyl) acetic acid 30CO(CH₂)₂CONH-(3- N-(3-methoxy-phenyl)- 170-172 1035 methoxy-phenyl)succinamic acid 31 CO(CH₂)₂CONH-(2,4- N-(2,4-difluoro-phenyl)- 190-1921040 difluorophenyl) succinamic acid 32 CO(CH₂)₂CO-(4-phenyl)-4-oxo-4-(4-phenyl-piperazin- 162-163 1075 piperazin-1-yl 1-yl)-butyricacid 33 COCH═CH-(pyridin-4-yl) 3-pyridin-4-yl-acrylic acid 210-212 961.134 COCH═CH-(pyridin-3-yl) 3-pyridin-3-yl-acrylic acid 157-159 961.1 35COCH═CH-(pyridin-2-yl) 3-pyridin-2-yl-acrylic acid 107-110 961.1 36COCH═CH-(1-(2- 3-[1-(2-methoxy-phenyl)-1H- 172-175 1057.2methoxy-phenyl)-1H- [1,2,3]triazol-4-yl]-acrylic [1,2,3]triazol-4-yl)acid 37 COCH═CH-(1-(3- 3-[1-(3-methoxy-phenyl)-1H- 148-151 1057.2methoxy-phenyl)-1H- [1,2,3]triazol-4-yl]-acrylic [1,2,3]triazol-4-yl)acid 38 COCH═CH-(1-(4-fluoro- 3-[1-(4-fluoro-phenyl)-1H- 198-200 1045.1phenyl)-1H-[1,2,3]triazol-4- [1,2,3]triazol-4-yl]-acrylic yl) acid 39COCH═CH-(1-(3-fluoro- 3-[1-(3-fluoro-phenyl)-1H- 188-190 1045.1phenyl)-1H-[1,2,3]triazol-4- [1,2,3]triazol-4-yl]-acrylic yl) acid 40COCH═CH-(1-(4- (E)-3-[1-(4-methoxy-phenyl)- 203-202 1057.2methoxy-phenyl)-1H- 1H-[1,2,3]triazol-4-yl]-acrylic [1,2,3]triazol-4-yl)acid 41 CO(CH₂)₂-phenyl 3-phenyl-propionic acid 140-142 962.1 42CO(CH₂)₂-(pyridin-2-yl) 3-pyridin-2-yl-propionic acid 116-118 963.1 43CO(CH₂)₂-(1-(4- 3-[1-(4-methoxy-phenyl)-1H- 182-184 1059.2methoxyphenyl)-1H- [1,2,3]triazol-4-yl]-propionic [1,2,3]triazol-4-yl)acid 44 CO(CH₂)₂-(1-(4-fluoro 3-[1-(4-fluoro-phenyl)-1H- 202-205 1047.2phenyl)-1H-[1,2,3]triazol-4- [1,2,3]triazol-4-yl]-propionic yl) acid 45CO(CH₂)₂-(pyridin-4-yl) 3-pyridin-4-yl-propionic acid 166-168 963.1 46CO(CH₂)₂-(3- 3-(3-methoxy-phenyl)- 172-174 992.1 methoxy)phenylpropionic acid 47 CO(CH₂)₂-(4- 3-(4-methoxy-phenyl)- 164-167 992.1methoxy)phenyl propionic acid 48 CO(CH₂)₂-(1-methyl 3-(1-m-tolyl-1H-172-174 1043.2 phenyl)-1H-[1,2,3]triazol-4-[1,2,3]triazol-4-yl)-propionic yl) acid 49 CO(CH₂)₂-(1-3-[1-(3-chloro-phenyl)- 176-178 1063.6 chlorophenyl)-1H- 1H[1,2,3]triazol-4-yl]- [1,2,3]triazol-4-yl) propionic acid 50CO(CH₂)₂-(3-(4-fluoro- 3-[3-(4-fluoro-phenyl)- 148-154 1048.1phenyl)-[1,2,4]oxadiazol-5- [1,2,4]oxadiazol-5-yl]- yl) propionic acid51 CO(CH₂)₂-(3-(3-bromo- 3-[3-(3-bromo-phenyl)- 158-160 1109.1phenyl)-[1,2,4]oxadiazol-5- [1,2,4]oxadiazol-5-yl]- yl) propionic acid52 CO(CH₂)₂-(3-(4-nitro- 3-[3-(4-nitro-phenyl)- 198-201 1075.2phenyl)-[1,2,4]oxadiazol-5- [1,2,4]oxadiazol-5-yl]- yl) propionic acid53 CO(CH₂)₂-(4-(pyridin-2- 3-(4-pyridin-2-yl-piperazin-1- 138-1401047.281 yl)-piperazinyl) yl)-propionic acid 54 CO(CH₂)₂-(3-cyano)phenyl3-(3-Cyano-phenyl)-propionic 170-172 987.1 acid 55COCH₂O-(3-chloro)phenyl 3-(3-Chloro-phenyl)-propionic 158-161 996.6 acid56 CO(CH₂)₂-(3,5- 3-(3,5-Dimethoxy-phenyl)- 118-120 1022.2dimethoxy)phenyl propionic acid 57 CO(CH₂)₂-(2,3-3-(2,3-Dimethoxy-phenyl)- 152-154 1022.2 dimethoxy)phenyl propionic acid58 CO(CH₂)₂-(3-(3-fluoro- 3-[3-(3-Fluoro-phenyl)- 166-170 1048.1phenyl)-[1,2,4]oxadiazol-5- [1,2,4]oxadiazol-5-yl]- yl) propionic acid59 CO(CH₂)₂-(3-(3-chloro- 3-[3-(3-Chloro-phenyl)- 158-160 1064.6phenyl)-[1,2,4]oxadiazol-5- [1,2,4]oxadiazol-5-yl]- yl) propionic acid60 CO(CH₂)₂-(3-(3-methoxy- 3-[3-(3-Methoxy-phenyl)- 148-150 1060.2phenyl)-[1,2,4]oxadiazol-5- [1,2,4]oxadiazol-5-yl]- yl) propionic acid61 CO(CH₂)₂-(3-(3,5- 3-[3-(3,5-Dimethoxy-phenyl)- 160-163 1090.2dimethoxy-phenyl)- [1,2,4]oxadiazol-5-yl]- [1,2,4]oxadiazol-5-yl)propionic acid 62 CO(CH₂)₂-(3-(4-chloro- 3-[3-(4-Chloro-phenyl)- 144-1461064.6 phenyl)-[1,2,4]oxadiazol-5- [1,2,4]oxadiazol-5-yl]- yl) propionicacid 63 CO(CH₂)₂-(3-(4-bromo- 3-[3-(4-Bromo-phenyl)- 152-154 1109.1phenyl)-[1,2,4]oxadiazol-5- [1,2,4]oxadiazol-5-yl]- yl) propionic acid64 CO(CH₂)₂-(3-(pyridin-4- 3-(3-Pyridin-4-yl- 156 1031.1yl)-[1,2,4]oxadiazol-5-yl) [1,2,4]oxadiazol-5-yl)- propionic acid 65CO(CH₂)₂-(4-(2- 3-(4-o-tolyl-piperazin-1-yl)- 170 1060.3methylphenyl)-piperazinyl) propionic acid 67 CO(CH₂)₂-(4-(3-3-[4-(3-Methoxy-phenyl)- 146 1076.3 methoxyphenyl)-piperazinylpiperazin-1-yl]-propionic acid 68 CO(CH₂)₂-(4-(2-3-[4-(2-Fluoro-phenyl)- 152 1064.2 fluorophenyl)-piperazinyl)piperazin-1-yl]-propionic acid 69 CO(CH₂)₂-(4-(pyrimidin-2-3-(4-pyrimidin-2-yl-piperazin- 170 1048.2 yl)-piperazinyl)1-yl)-propionic acid 70 CO(CH₂)₂-(1-(2- 3-[1-(2-fluoro-phenyl)-1H- 1621047.2 fluorophenyl)-1H- [1,2,3]triazol-4-yl]-propionic[1,2,3]triazol-4-yl) acid 71 CO(CH₂)₂-(4- 3-(4-trifluoromethyl-phenyl)-168 1030.1 trifluoromethyl)phenyl propionic acid 72CO(CH₂)₂-(3-(2-fluoro-5- 3-[3-(2-fluoro-5-methoxy- 158 1078.2methoxy-phenyl)- phenyl)-[1,2,4]oxadiazol-5- [1,2,4]oxadiazol-5-yl)yl]-propionic acid 73 CO(CH₂)₂-(3-phenyl-4H- 3-(4-phenyl-4H-imidazol-1-172-174 1028.2 imidazol-1-yl) yl)-propionic acid 74 COCH₂NHCONH-phenyl(3-phenyl-ureido)-acetic acid 164-168 1006.1 75 CO(CH₂)₂-(4-3-(4-[1,2,3]triazol-1-yl- 180-183 1029.2 ([1,2,3]triazol-1-yl)phenyl)phenyl)-propionic acid 76 CO(CH₂)₂-(4-cyano)phenyl3-(4-Cyano-phenyl)-propionic 168-170 987.1 acid 77 CO(CH₂)₂-(2,5-3-(2,5-dimethoxy-phenyl)- 166-169 1022.2 dimethoxy)phenyl propionic acid78 CO(CH₂)₂- 3-benzo[1,3]dioxol-5-yl- 138-140 1006.1(benzo[1,3]dioxol-5-yl) propionic acid 79 CO(CH₂)₂-(3,5-3-(3,5-dimethoxy-phenyl)- 170-174 1022.1 dimethoxy)phenyl propionic acid80 CO(CH₂)₂-(1-(2,4- 3-[1-(2,4-difluoro-phenyl)- 158-161 1065.2difluorophenyl)-1H- 1H-[1,2,3]triazol-4-yl]- [1,2,3]triazol-4-yl)propionic acid 81 CO(CH₂)₂-(1-(3,4- 3-[1-(3,4-difluoro-phenyl)- 172-1751065.2 difluorophenyl)-1H- 1H-[1,2,3]triazol-4-yl]- [1,2,3]triazol-4-yl)propionic acid 82 CO(CH₂)₂-(1-(2,3,4- 3-[1-(2,3,4-trifluoro-phenyl)-108-110 1083.1 trifluorophenyl)-1H- 1H-[1,2,3]triazol-4-yl]-[1,2,3]triazol-4-yl) propionic acid 83 CO(CH₂)₂-(1-(2-fluoro-4-3-[1-(2-fluoro-4-methyl- 138-141 1061.2 methyl-phenyl)-1H-phenyl)-1H-[1,2,3]triazol-4- [1,2,3]triazol-4-yl) yl]-propionic acid 84CO(CH₂)₂-(1-(2-fluoro-4- 3-[1-(2-fluoro-4-methoxy- 168.000 1077.2methoxy-phenyl)-1H- phenyl)-1H-[1,2,3]triazol-4- [1,2,3]triazol-4-yl)yl]-propionic acid 85 CO(CH₂)₂-(1-(2,3-difluoro-3-[1-(4-Ethoxy-2,3-difluoro- 136-139 1109.2 4-ethoxy-phenyl)-1H-phenyl)-1H-[1,2,3]triazol-4- [1,2,3]triazol-4-yl) yl]-propionic acid 86CO(CH₂)₂-(4-(4-cyano- 3-[4-(4-Cyano-[1,2,3]triazol- 144-148 1054.2[1,2,4]triazol-1-yl)phenyl) 1-yl)-phenyl]propionic acid 87CO(CH₂)₂CONH-(3- N-(3-Methoxy-phenyl)- 170-173 1035.2 methoxy-phenyl)succinamic acid 88 CO(CH₂)₂-(4-(imidazol-1- 3-(4-Imidazol-1-yl-phenyl)-168-171 1028.2 yl)phenyl) propionic acid 89 CO(CH₂)₂-(4-3-(4-[1,2,4]triazol-1-yl- 185-187 1029.2 ([1,2,4]triazol-1-yl)phenyl)phenyl)-propionic acid 90 CO(CH₂)₂CONH-(2- N-(2-Methoxy-phenyl)- 186-1881035.2 methoxy-phenyl) succinamic acid 91 CO(CH₂)₂CONH-(2,4-N-(2,4-Difluoro-phenyl)- 190-192 1041.1 difluorophenyl) succinamic acid92 CO(CH₂)₂CO-(4-(4-fluoro- 4-[4-(2-Fluoro-phenyl)- 160-164 1092.2phenyl)piperazin-1-yl) piperazin-1-yl]-4-oxo-butyric acid 93COCH₂NHCONH-phenyl (3-Phenyl-ureido)-acetic acid 164-168 1006.1 94COCH₂-(benzo[1,3]dioxol- benzo[1,3]dioxol-5-yl-acetic 170-174 992.15-yl) acid 95 COCH₂NHCONH-(4- [3-(4-fluoro-phenyl)-ureido]- 172-1751024.1 fluorophenyl) acetic acid 96 COCH₂NHCONH-(3-[3-(3-chloro-4-methyl- 176-178 1054.6 chloro-4-methylphenyl)phenyl)-ureido]-acetic acid 97 COCH₂O-phenyl phenoxy-acetic acid 160-164964.1 98 COCH₂S-phenyl phenylsulfanyl-acetic acid 158-160 980.2

Example-99 Compound of Formula I-c where T isCO(CH₂)₂-(1-(3,5-difluoro-phenyl)-1H-[1,2,3]triazol-4-yl), R₁ is CH₃

To a solution of3-[1-(3,5-difluoro-phenyl)-1H-[1,2,3]triazol-4-yl]-propionic acid (0.288g, 1.13 mmol) in dichloromethane (50 ml) was addeddicyclohexylcarbodiimide (0.486 g, 2.35 mmol) and1-hydroxy-benzotriazole (0.040 g, 0.296 mmol) at an ambient temperature.The reaction mixture was stirred further for 1 h. To this reactionmixture then added Example 5 (1.0 g, 0.946 mmol) and followed bydimethyl amino pyridine (0.033 g, 0.270 mmol) at an ambient temperature.The reaction mixture was further stirred for 1 h. The reaction mixturewas filtered and the filtered solid was washed with dichloromethane (10ml). The combined filtrate was evaporated under reduced pressure toprovide a thick liquid (1.1 g), which was used as it is withoutpurification for further reaction.

To a solution of above thick liquid (1.1 g, 0.876 mmol) in THF (20 ml)was added 70% hydrogen fluoride in pyridine (72 μl, 2.52 mmol) at roomtemperature under inert atmosphere. The resulting solution was furtherfor 15 h. The solvent evaporated under reduced pressure. The residue wasdissolved into water (30 ml) and washed with diethyl ether (3×25 ml).The aqueous layer upon saturation with sodium chloride a white solid wasprecipitated out, it was filtered and dried. The white solid obtainedwas triturated with diethyl ether to give the title compound as a whitesolid (0.400 g).

Using the above procedure following examples were synthesized by usingthe corresponding carboxylic acid.

MP Mass Example T Carboxylic acid (° C.) M + 1 100 CO(CH₂)₂-(1-(2-3-[1-(2-Methoxy-phenyl)- 176-178 1059 methoxy)phenyl)-1H-1H-[1,2,3]triazol-4-yl]- [1,2,3]triazol-4-yl) propionic acid 101CO(CH₂)₂-(1-(3-fluoro- 3-[1-(3-fluoro-phenyl)-1H- 186-188 1047phenyl)-1H-[1,2,3]triazol-4- [1,2,3]triazol-4-yl]propionic yl) acid 102CO(CH₂)₂-(1-(3,4-difluoro- 3-[1-(3,4-difluoro-phenyl)- 168-170 868phenyl)-1H-[1,2,3]triazol-4- 1H-[1,2,3]triazol-4-yl]- yl) propionic acid103 CO(CH₂)₂-(1-(3,5- 3-[1-(3,5-dimethoxy- 180-182 1089dimethoxy-phenyl)-1H- phenyl)-1H-[1,2,3]triazol-4- [1,2,3]triazol-4-yl)yl]-propionic acid 104 CO(CH₂)₂-(1-(3-methoxy- 3-[1-(3-methoxy-phenyl)-186-187 1032 phenyl)-1H-[1,2,3]triazol-4- 1H-[1,2,3]triazol-4-yl]- yl)propionic acid 105 CO(CH₂)₂-(1-(pyridin-3- 3-(1-pyridin-3-yl-1H- 170-1721030 yl)-1H-[1,2,3]triazol-4-yl) [1,2,3]triazol-4-yl)- propionic acid

Example-106 Compound of Formula I-c where T isCO(CH₂)₂-(3-(2-fluoro-5-methoxy-phenyl)-[1,2,4]oxadiazol-5-yl), R₁ isCH₃

To a solution of3-[3-(2-fluoro-5-methoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid(0.413 g, 1.89 mmol) in dichloromethane (50 ml) was addeddicyclohexylcarbodiimide (0.486 g, 2.35 mmol) and1-hydroxy-benzotriazole (0.040 g, 0.296 mmol) at an ambient temperature.The reaction mixture was stirred further for 1 h. To this reactionmixture then added Example 5 (1.0 g, 0.946 mmol) and followed bydimethyl amino pyridine (0.033 g, 0.270 mmol) at an ambient temperature.The reaction mixture was further stirred for 1 h. The reaction mixturewas filtered and the filtered solid was washed with dichloromethane (10ml). The combined filtrate was evaporated under reduced pressure toprovide a thick liquid (1.1 g), which was used as it is withoutpurification for further reaction.

To a solution of above thick liquid (1.1 g, 0.876 mmol) in THF (20 ml)was added 70% hydrogen fluoride in pyridine (65 μl, 2.27 mmol) at roomtemperature under inert atmosphere. The resulting solution was furtherfor 15 h. The solvent evaporated under reduced pressure. The residue wasdissolved into water (30 ml) and washed with diethyl ether (3×25 ml).The aqueous layer upon saturation with sodium chloride a white solid wasprecipitated out, it was filtered and dried. The white solid obtainedwas triturated with diethyl ether to give the title compound as a whitesolid (0.325 g).

Using the above procedure following examples were synthesized by usingthe corresponding carboxylic acid.

MP Mass Example T Carboxylic acid (° C.) M + 1 107 CO(CH₂)₂-(3-phenyl-3-(3-Phenyl-[1,2,4]oxadiazol-5- 162-166 1030 [1,2,4]oxadiazol-5-yl)yl)-propionic acid 108 CO(CH₂)₂-(3- 3-(3-Naphthalen-2-yl- 138-142 1080naphthalen-2-yl- [1,2,4]oxadiazol-5-yl)-propionic [1,2,4]oxadiazol-5-yl)acid 109 CO(CH₂)₂-(3-(pyridin- 3-(3-Pyridin-3-yl- 149-150 10313-yl)-[1,2,4]oxadiazol- [1,2,4]oxadiazol-5-yl)-propionic 5-yl) acid 110CO(CH₂)₂-[3-(4- 3-[3-(4-Methoxy-phenyl)- 132-134 1060 methoxyphenyl)-[1,2,4]oxadiazol-5-yl]-propionic [1,2,4]oxadiazol-5-yl] acid

Example-111 Compound of Formula I-c where T isCH₂-(5-methyl-[1,2,4]oxadiazol-3-yl), R₁ is CH₃

Step A: To a stirred solution of Example 5 (1.0 g, 0.95 mmol) in1,4-dioxan (10 ml) was added N,N-dimethylformamide dimethylacetal (2 ml)and heated at 70° C. for 2 h. After completion of reaction solvent wasevaporated under vacuum, water was added to the crude reaction mass andextracted with ethyl acetate (50 ml×3). Combined organic layer was driedover anhydrous sodium sulphate and then evaporated yielding crude solid.It was then purified by column chromatography using (Ethylacetate:n-hexane; 20:80) as a mobile phase. Pale solid compound wasisolated Yield: 550 mg, (55%).

Step B: The compound obtained in Step A (550 mg, 0.50 mmol) wasdissolved in acetonitrile (10 ml). 70% HF-Pyridine solution (44 μl, 3.0equi.) was added to the above solution and stirred at room temperaturefor overnight under N₂ atmosphere. After completion of reaction solventwas evaporated under vacuum to obtain crude solid. Water (20 ml) wasadded to the crude product and then extracted with dichloromethane (30ml×3). Combined organic layer was dried over sodium sulphate andevaporated under vacuum to obtain crude white solid. It was thenpurified by column chromatography using CHCl₃:MeOH; 80:20) as a mobilephase to obtain title compound as white solid (Yield: 190 mg, 44%), MS854 (M+H)⁺ Mp: 213-214° C.

Example-112 Compound of Formula I-c where T is CH₂CONH-(3-chloro)phenyl,R₁ is CH₃

Step-1: To the stirred solution of Example 5 (1.00 g, 0.94 mmol) inbenzene (20 ml) was added sodium hydride (47 mg, 1.13 mmol, 60%suspension in mineral oil) at 25-30° C. temperature and stirred for 30min. 2-Bromo-N-(3-chloro-phenyl)-acetamide (0.25 g, 1.04 mmol) was addedto reaction mixture and stirred for 1 hour at an 25-30° C. temperature.The reaction mixture was then poured in aqueous saturated ammoniumchloride solution (30 ml). Organic layer was dried over Na₂SO₄. It waspurified using silica gel column chromatography (10% Acetone:Hexane) toprovide step-1 product as solid in 75% (0.87 g) yield. MS: m/z: 1229(M+1)

Step-2: A mixture of step-1 product and (0.80 g, 0.65 mmol) 70% HF inpyridine (55 μl, 1.95 mmol) in THF (15 ml) was stirred under inertatmosphere for 15 h at 25-30° C. temperature. The solvent was evaporatedunder vacuum to provide a residue. The residue was dissolved in ethylacetate (15 ml) and washed with water (2×10 ml). The organic layer wasdried over Na₂SO₄ and evaporated under vacuum to provide crude solidwhich on trituration in diethyl ether afforded pale yellow solid as thetitle compound Example in 65% (0.42 g) yield. Mp: 128-131° C., Mass:M/z: 997.1 (M+1).

Following examples were prepared by using above procedure and by usingreactant A.

MP Mass Example T Reactant (A) (° C.) (M + 1) 113 CH₂CONH₂2-bromo-acetamide 207-210 887.1 114 CH₂CONH-(2-methoxy)phenyl2-Bromo-N-(2-methoxy- 188-190 993.1 phenyl)-acetamide 115CH₂CONH-(3-methoxy)phenyl 2-Bromo-N-(3-methoxy- 190-194 993.1phenyl)-acetamide 116 CH₂CONH-(2-fluoro)phenyl2-Bromo-N-(2-fluoro-phenyl)- 184-187 981.1 acetamide 117CH₂CONH-(3-fluoro)phenyl 2-Bromo-N-(3-fluoro-phenyl)- 182-185 981.1acetamide 118 CH₂CONH-(4-fluoro)phenyl 2-Bromo-N-(4-fluoro-phenyl)-190-194 981.1 acetamide 119 CH₂CONH-(2,4-difluoro)phenyl2-Bromo-N-(2,4-difluoro- 178-182 999.1 phenyl)-acetamide 120CH₂CONH-(3,4-difluoro)phenyl 2-Bromo-N-(3,4-difluoro- 196-199 999.1phenyl)-acetamide 121 CH₂CONH-(2,3,4- 2-Bromo-N-(2,3,4-trifluoro-190-194 1017.1 trifluoro)phenyl phenyl)-acetamide 122 CH₂CONH-(3,5-2-Bromo-N-(3,5-dimethoxy- 184-187 1023.1 dimethoxy)phenylphenyl)-acetamide 123 CH₂CONH-cyclopropyl 2-Bromo-N-cyclopropyl- 180-183927.1 acetamide 124 CH₂CON(CH₃)-(3-fluoro)phenyl2-Bromo-N-(3-fluoro-phenyl)- 174-178 995.1 N-methyl-acetamide 125CH₂CON(CH₃)-(4- 2-Bromo-N-(4-chloro- 198-201 1011.1 chloro)phenylphenyl)-N-methyl-acetamide 126 CH₂CONH-(3-(pyrazol-1-yl)-2-Bromo-N-(6-pyrazol-1-yl- 172-175 1030.1 pyridin-5-yl)pyridin-3-yl)-acetamide 127 CH₂-(1-(4-fluorophenyl)-1H-4-Bromomethyl-1-(4-fluoro- 158-160 1008.1 [1,2,3]-triazol-5-yl)phenyl)-1H-[1,2,3]-triazole 128 CH₂-(1-(3-fluorophenyl)-1H-4-bormomethyl-1-(3- 210-212 1008.1 [1,2,3]-triazol-5-yl)fluorophenyl)-1H-[1,2,3]- triazole 129 CH₂-(1-(3,5-difluoro phenyl)-4-bromomethyl-1-(3,5- 191-193 1026.1 1H-[1,2,3]-triazol-5-yl)difluoro-phenyl)-1H-[1,2,3]- trizole 130 CH₂-(1-(3,4-difluoro phenyl)-4-bromomethyl-1-(3,4- 190-192 1026.1 1H-[1,2,3]-triazol-5-yl)difluoro-phenyl)-1H-[1,2,3]- trizole 131 CH₂-(1-(3,4,5-trifluorophenyl)-4-bromomethyl-1-(2,3,4- 180-182 1044.1 1H-[1,2,3]-triazol-5-yl)trifluoro-phenyl)-1H-[1,2,3]- trizole 132 CH₂-(1-(3-chlorophenyl)-1H-4-bromomethyl-1-(3-chloro- 191-193 1023.1 [1,2,3]-triazol-5-yl)phenyl)-1H-[1,2,3]-trizole 133 CH₂-(5-(pyridin-2-yl)-[1,2,4]-2-(3-bromomethyl-[1,2,4]- 149-151 990.1 oxadiazol-3-yl)oxadiazole-5-yl)-pyridine

Example-134 Compound of Formula I-c where T is CH₂-phenyl, R₁ is CH₃

To the stirring solution of Example 5 (0.56 mmol) in benzene (10 ml) wasadded NaH (0.62 mmol) and stirred it for 30 min. To this stirringsolution, benzyl bromide (0.68 mmol) was added and stirred the reactionmixture for 4 hours at 60° C. The reaction mixture was allowed to comeat room temperature and then poured in water (20 ml). Separated organiclayer and dried over Na₂SO₄. Purified it with silica gel columnchromatography (20% Ethyl acetate:Hexane). Yield 54%. The above product(0.31 mmole) was taken in tetrahydrofuran (5 ml) and added HF-Pyridinecomplex (1.24 mmole). Stirred at room temperature for overnight. Thereaction mixture was concentrated and water was added. Extracted theproduct in dichloromethane (2×10 ml). Dried it (Na₂SO₄) and concentratedto give title compound in yield 44%. MS 920 (M+H).

Using the above procedure following examples were synthesized by usingthe corresponding Reagent A.

Ex- am- M.P. Mass ple T Reagent A (° C.) M + 1 135 CH₂C(CH₃)═CH₂3-bromo-2-methyl- 184-186 884 propene 136 CH₂-(4-nitro)phenyl4-nitrobenzyl bromide 160-164 965 137 CH₂CH₂-(4-(pyridin-1-(2-bromoethyl)-4- 130-132 1019 2-yl)piperazinyl)pyridin-2-yl-piperazine 138 CH₂CH═CH-(2,3- 6-bromo-1,4-benzo 176-1781004 dihydro- dioxane benzo[1,4]dioxin-6-yl) 139 CH₂CH═C(CH₃)₂1-bromo-3-methyl-but- 195-197 899.1 2-ene 140 CH₂CH₂CH═CH₂4-bromo-but-1-ene 194-196 885.1 141 CH₂-(4-methyl- 4-methyl-benzyl178-180 935.1 phenyl) bromide 142 CH₂-(2-methyl henyl) 2-methyl benzyl160-162 935.1 bromide 143 CH₂-(3-methoxy 3-methoxy-benzyl 168-170 951.1phenyl) bromide 144 CH₂-(2-fluorophenyl) 2-fluoro-benzyl 172-174 939.1bromide 145 CH₂-(4-bromophenyl) 4-bromo-benzyl 168-170 1000.1 bromide146 CH₂-(2,4- 2,4-difluoro-benzyl 166-168 957.1 difluorophenyl) bromide147 CH₂-(2,5- 2,5-difluoro-benzyl 166-168 957.1 difluorophenyl) bromide148 CH₂CO₂CH₂CH₃ ethyl bromoacetate 190-192 917.1 149 CH₂CO-(4-phenyl-2-bromo-1-(4-phenyl- 179-181 1033.1 piperazin-1-yl) piperazin-1-yl)-ethanone 150 CH₂CO-(4-(2- 2-bromo-1-[4-(2- 194-196 1051.1 fluorophenyl)-fluoro-phenyl)- piperazin-1-yl) piperazin-1-yl]- ethanone

Example 151 Compound of Formula I-c where T is CH₂CN, R₁ is CH₃

Step A: To the stirring solution of the Example 5 (15.52 mmol) inacetone was added K₂CO₃ (1.2 eq), bromo acetonitrile (1.1 eq) andrefluxed it for 48 hours. The reaction mixture was concentrated undervacuo. Water was added and filtered the residue. Dried it and purifiedit with column chromatography (EA; Hexane 20:80). Yield 77%.

Step B: To the stirring solution of the compound obtained in step B(0.52 mmol) in dry acetonitrile was added 70% HF in Pyridine complex(3.5 eq) The resulting mixture was stirred for 16 hours at roomtemperature under nitrogen atmosphere. The reaction mixture evaporatedunder vacuo. Water was added and extracted it in chloroform. Dried itover Na₂SO₄ and concentrated it. The residue was crystallized fromethanol:water (30:70) to give the title compound in yield 67%. MS 869(M+H)⁺. Mp: 172-174° C.

Example 152 Compound of Formula I-c where T is CH₂C(NH₂)═N—OH, R₁ is CH₃

Step-1: To the solution of compound obtained in step A of above example(5.0 g, 4.55 mmol) in methanol (40 ml) was added hydroxylaminehydrochloride (3.25 g), and sodium bicarbonate (4.21 g, 50.1 mmol)stirred for 12 hr at room temperature. The reaction mass wasconcentrated under vacuum to obtain crude solid. The crude solid wasstirred with water (100 ml). Solid separated was filtered under suctionand dried under vacuum to provide step-1 product in 93% (4.8 g) yield.Mass: m/z: 1130 (M+1).

Step-2: A mixture of step-1 product (1.0 g, 0.9 mmol) and 70% hydrogenfluoride in pyridine (77 μl, 2.6 mmol) in THF (15 ml) was stirred underinert atmosphere at a temperature between 25-30° C. for 15 h. Thesolvent was evaporated under vacuum and the residue obtained wasdissolved in ethyl acetate (25 ml) and washed with water (2×10 ml). Thecombined organic layer was dried over Na₂SO₄ and evaporated underreduced pressure to provide crude solid which on trituration in diethylether afforded pale yellow solid as the title compound in 60% (0.65 g)yield. Mp: 168-170° C. Mass: m/z: 903.1 (M+1).

Example-153 Compound of Formula I-c where T is CH₂CH═CH₂, R₁ is CH₃

Step A: To the stirring solution of Example 5 (0.56 mmol) in Toluene (10ml) was added Potassium tert butoxide (0.62 mmol) and stirred it for 20min. To this stirring solution, allyl bromide (0.68 mmol) was added andstirred the reaction mixture for 2 hours at room temperature. Thereaction mixture was then poured in water (20 ml). Separated organiclayer and dried over Na₂SO₄. Purified it with silica gel columnchromatography (20% Ethyl acetate:Hexane). Yield 74%.

Step B: The product from step A (0.31 mmol) was taken in tetrahydrofuran(5 ml) and added HF-Pyridine complex (1.24 mmol). Stirred at roomtemperature for overnight. The reaction mixture was concentrated andwater was added. Extracted the product in dichloromethane (2×10 ml).Dried it (Na₂SO₄) and concentrated to give title compound in yield 60%.MS 867 (M+H). M.P 194-196° C.

Example-154 Compound of Formula I-c where T is CH₂CH═CH-phenyl, R₁ isCH₃

Step-A: To the stirred solution of compound obtained in Step A of aboveexample (1.5 g, 1.36 mmol) in DMF (15 ml) was added sodium acetate (0.24ml, 2.73 mmol) at 25-30° C. temperature. To the above solution tetrakistriphenylphosphine palladium (0) (0.15 g, 0.13 mmol) and bromobenzene(0.31 g) were added and the reaction mixture was stirred at 120° C.temperature for 12 hours. The reaction mixture was quenched by pouringin aqueous saturated ammonium chloride solution (20 ml). The mixture wasextracted with ethyl acetate (3×50 ml). Combined organic layer was driedover Na₂SO₄ to provide a residue. The residue was purified by usingsilica gel column chromatography (10% Acetone:Hexane) to provide step-1product as a solid in 65% (1.0 g) yield. MS: m/z: 1226 (M+1).

Step-B: A mixture of step-2 product (0.90 g, 0.73 mmol) and 70% hydrogenfluoride in pyridine (63 μl, 2.20 mmol) in THF (15 ml) was stirred underinert atmosphere for 15 h. The solvent was evaporated under vacuum toprovide a residue. The residue was dissolved in ethyl acetate (15 ml)and washed with water (2×10 ml). The organic layer was dried over Na₂SO₄and evaporated under vacuum to provide crude solid which on triturationin diethyl ether afforded white solid as the title compound example in55% (0.40 g) yield. Mass: m/z: 998.1 (M+1) Mp: 196-199° C.

Following examples were prepared by using above procedure and by usingreactant A.

MP Mass Example U Reactant A ° C. M + 1 155 (2-methoxy)phenyl1-bromo-2-methoxy-benzene 120 976.2 156 (3-fluoro)phenyl1-bromo-3-fluoro-benzene 182 964.1 157 (4-cyano)phenyl4-bromo-benzonitrile 160 971.1 158 (3-hydroxymethyl)phenyl(3-bromophenyl)-methanol 125 976.2 159 (4-trifluoromethyl)phenyl1-bromo-4-trifluoromethyl-benzene 96 1014.1 160(3-trifluoromethyl)phenyl 1-bromo-3-trifluoro methyl-benzene 176 1014.1161 (3-acetoxy)phenyl 1-(4-bromophenyl)-ethanone 155 988.2

Example-162 Compound of Formula I-c where T isCH₂-(3-(5-fluoro-2-methoxyphenyl)-isoxazol-5-yl), R₁ is CH₃

Step-1: To the stirred solution of compound obtained in Step A ofexample 153 (1.5 g, 1.36 mmol) in toluene (15 ml) was addedtriethylamine (0.38 ml, 2.73 mmol) followed by 2-methoxy-5-fluoroimidoyl chloride (0.34 g, 2.05 mmol) at 25-30° C. temperature. Thereaction mixture was stirred at 90° C. temperature for 12 hours. It wasdiluted with ethyl acetate (50 ml) followed by addition of water (20ml). Organic layer was dried over Na₂SO₄, evaporated under vacuum toprovide a residue. The residue was purified by using silica gel columnchromatography (10% Acetone:Hexane) to afford step-1 product as a solidin 70% (1.2 g) yield. MS 1264.1 (M+1).

Step-2: A mixture of step-1 product (1. g, 0.79 mmol) and 70% hydrogenfluoride in pyridine (68 μl, 2.37 mmol) in THF (15 ml) was stirred underinert atmosphere for 15 h. The solvent was evaporated under vacuum andthe residue obtained was dissolved in ethyl acetate (25 ml) and washedwith water (2×10 ml). The organic layer was dried over Na₂SO₄ andevaporated under vacuum to provide crude solid which upon triturationwith diethyl ether afforded pale yellow solid as the title compoundexample in 60% (0.49 g) yield. Mass: M/z: 950.1 (M+1). Mp: 192-194° C.

Example-163 Compound of Formula I-c where T is CH₂C≡CH, R₁ is CH₃

Step A: To the stirring solution of Example 5 (0.56 mmol) in Toluene (10ml) was added Potassium tert butoxide (0.62 mmol) and stirred it for 20min. To this stirring solution, 3allyl bromide (0.68 mmol) was added andstirred the reaction mixture for 2 hours at room temperature. Thereaction mixture was then poured in water (20 ml). Separated organiclayer and dried over Na₂SO₄. Purified it with silica gel columnchromatography (20% Ethyl acetate:Hexane). Yield 78%.

Step B: The product from step A (0.31 mmole) was taken intetrahydrofuran (5 ml) and added HF-Pyridine complex (1.24 mmole).Stirred at room temperature for overnight. The reaction mixture wasconcentrated and water was added. Extracted the product indichloromethane (2×10 ml). Dried it (Na₂SO₄) and concentrated to givetitle compound in yield 60%. MS 868 (M+H). M.P 168-170° C.

Example-164 Compound of Formula I-c where T is CH₂C≡C-(3-cyano-phenyl),R₁ is CH₃

Step-1: To the solution of compound obtained in step A of above example(1.4 g, 1.23 mmol) in DMF (40 ml) was added cesium carbonate (0.63 g,3.2 mmol), bis-triphenylphosphine Palladium (II) chloride (0.10 g, 0.13mmol), cuprous Iodide (0.05 g, 0.26 mmol) followed by 3-iodobenzonitrile(0.29 g, 1.27 mmol). The reaction mixture was stirred at 25-30° C.temperature under nitrogen atmosphere for 12 hrs. it was quenched withaddition of ice-cold water (15 ml) to provide a suspension. Solid wasfiltered & dried under vacuum. The solid was purified by using silicagel column chromatography (20% ethyl acetate-Hexane) to provide step-1product as a solid in 33% (0.5 g) yield. Mass: m/z: 1198 (M+1).

Step-2: A mixture of step-1 product (0.5 g, 0.41 mmol) and 70% hydrogenfluoride in pyridine (1.0 mmol) in THF (10 ml) was stirred under inertatmosphere at 25-30° C. temperature for 15 hr. The solvent wasevaporated under vacuum, obtained residue was dissolved in ethyl acetate(15 ml) and washed with water (2×10 ml). The organic layer was driedover Na₂SO₄ and evaporated under vacuum to provide crude solid which ontrituration in diethyl ether afforded off white solid as the titlecompound in 19% (0.075 g) yield. Mass: m/z: 970.1 (M+1). Mp: 158-159° C.

Following examples were prepared by using above procedure and by usingreactant A.

Ex- MP Mass ample T Reactant A ° C. (M + 1) 165 CH₂C≡C-phenylIodo-benzene 150-151 945.1 166 CH₂C≡C-(3-methyl)phe- 3-methyl-iodo-194-195 959.1 nyl benzene

Example-167 Compound of Formula I-c where T is CONH-phenyl, R₁ is CH₃

Step-1: To the stirred solution of Example-5 (0.75 g, 0.70 mmol) indichloromethane (40 ml) was added phenylisocyanate (0.12 ml) at 25-30°C. temperature. The reaction mixture was stirred further for 2 h. Themixture was quenched by addition of water (20 ml) and extracted withdichloromethane (2×20 ml). Combined organic layer was dried over Na₂SO₄and concentrated under vacuum to obtain crude solid. It was purified byusing silica gel column chromatography (10% Acetone:n-Hexane) to furnishstep-1 product as a pale yellow solid in 55% (0.48 g) yield. Mass: m/z:1226 (M+1).

Step-2: A mixture of step-1 product (0.47 g, 0.38 mmol) and 70% hydrogenfluoride in pyridine (32 μl, 1.14 mmol) in THF (10 ml) was stirred underinert atmosphere for 15 h. The solvent was evaporated and the residueobtained was dissolved in ethyl acetate (15 ml) and washed with water(2×10 ml). The organic layer was dried over Na₂SO₄ and evaporated undervacuum to provide crude solid which on trituration in diethyl etherafforded title compound as a pale yellow solid in 60% (0.28 g) yield.Mp: 192-194° C., Mass: m/z: 950.1 (M+1).

Example-168 Compound of Formula I-c where T is CONH-(4-ethyl-phenyl), R₁is CH₃

Using above procedure and by using 4-ethyl-phenyl isocyanate in theplace of phenyl isocyanate the title compound was prepared. Mp: 152-155°C., Mass: m/z: 978.1.

Example-169 Compound of Formula I-c where T is CH₂CH₂CH₃, R₁ is CH₃

Step-A: A stirred suspension of product obtained from the Step A ofExample 153 (1 g, 0.9 mmol) and 10% palladium on carbon (100 mg)) intetrahydrofuran (10 ml) was stirred under atmospheric hydrogen pressureat 25-30° C. temperature for 12 hours. The reaction mixture was filteredover celite bed, and filtrate was evaporated under vacuum to providestep-1 product as a white solid in 90% (0.9 g) yield. It was used assuch for the next reaction. Mass: m/z: 1101.1 (M+1).

Step-B: A mixture of step-1 product (0.9 g, 0.82 mmol) and 70% hydrogenfluoride in pyridine (24 μl, 2.5 mmol) in THF (10 ml) was stirred underinert atmosphere for 15 h. The solvent was evaporated and the residueobtained was dissolved in ethyl acetate (15 ml) and washed with water(2×10 ml). The organic layer was dried over Na₂SO₄ and evaporated undervacuum to provide crude solid which on trituration in diethyl etherafforded pale yellow solid title compound in 50% (70 g) yield. Mp:182-184° C. Mass: m/z: 873.1 (M+1).

Following examples were prepared by using above procedure and by usingthe corresponding unsaturated compound

Starting Mp Example T material (° C.) Mass (M + 1) 170 CH₂CH(CH₃)₂Example 135 210-212 887.1 171 CH₂CH₂CH(CH₃)₂ Example 139 184-186 901.1

Example-172 Compound of Formula I-e where Het is [1,2,4]-oxadiazol-3-yl

Step A: To a stirred solution of Example 7 (1.0 g, 1.3 mmol) in (10 ml)1,4-dioxan was added (2 ml) N,N dimethylformamide dimethylacetal andheated at 70° C. for 3 h. After completion of reaction solvent wasevaporated under vacuum, water (30 ml) was added to the crude reactionmass and extracted with ethyl acetate (50 ml×3). Combined organic layerwas dried over anhydrous sodium sulphate and then evaporated yieldingcrude solid. It was then purified by column chromatography using (EthylAcetate:n-hexane; 35:65) as a mobile phase. Pale solid was isolated.Yield: 450 mg, (45%).

Step B: To a stirred solution of the compound obtained in step A (450mg, 0.6 mmol) in dichloromethane (10 ml) was added Dess MartinPeriodinane reagent (2.0 ml, 1.2 equi., 15% solution) under N₂atmosphere at room temperature for 30 min. After completion of reaction,additional 25 ml of dichloromethane was added and then quenched with 30ml saturated aqueous solution of sodium thiosulphate:sodium bicarbonate.Organic layer was dried over anhydrous sodium sulphate and thendistilled off under vacuum to obtain pale yellow solid. It was thenpurified by column chromatography using (Ethyl Acetate:n-Hexane; 30:70)as a mobile phase. Crystalline solid was isolated. Yield: 250 mg, (52%).

Step C: The compound obtained in step B (250 mg, 0.30 mmol) wasdissolved in acetonitrile (10 ml). 70% HF-Pyridine solution (18 μl, 2.0euqi.) was added to the above solution and stirred at room temperaturefor overnight under N₂ atmosphere. After completion of reaction solventwas evaporated under vacuum to obtain crude product. Water (20 ml) wasadded to the crude product and extracted with dichloromethane (25 ml×3).Combined organic layer was dried over sodium sulphate and evaporatedunder vacuum to obtain crude white solid. It was then purified by columnchromatography using CHCl₃:MeOH (90:10) as a mobile phase to obtaintitle compound as white solid compound. Yield: 120 mg, (56%) MS: 681.1(M+H)⁺. Yield: 0.185 mg, (55%), M.P.: 208-210° C.

Example-173 Compound of Formula I-e where Het is(5-trifluoromethyl)-[1,2,4]-oxadiazol-3yl

Step A: To a stirring solution of Example 9 (1.0 gm, 1.3 mmol) indichloromethane (25 ml) was added trifluoroacetic anhydride (0.365 ml,2.6 mmol) and triethyl amine (0.550 ml, 3.9 mmol). The resultingreaction mixture was heated at 45° C. for 12 h water (25 ml) was addedto and extracted with dichloromethane (2×20 ml). Combined organic layerwas dried over Na₂SO₄ and evaporated under reduced pressure. Resultingcrude residue was purified by using column chromatography (15%Acetone-Hexane) to afford pale solid. Yield: 0.6 gm.

Step B: To a stirred solution of the compound obtained in step A (580mg, 0.7 mmol) in dichloromethane (10 ml) was added Dess MartinPeriodinane reagent (2.4 ml, 1.2 equi., 15% solution) under N₂atmosphere at room temperature for 30 min. After completion of reaction,additional 25 ml of dichloromethane was added and then quenched with 30ml saturated aqueous solution of sodium thiosulphate:sodium bicarbonate.Organic layer was dried over anhydrous sodium sulphate and thendistilled off under vacuum to obtain pale yellow solid. It was thenpurified by column chromatography using (Ethyl Acetate:n-Hexane; 30:70)as a mobile phase. Crystalline solid was isolated. Yield: 300 mg, (52%).

Step C: The compound obtained in step B (280 mg, 0.35 mmol) wasdissolved in acetonitrile (10 ml). 70% HF-Pyridine solution (19 μl, 2.0euqi.) was added to the above solution and stirred at room temperaturefor overnight under N₂ atmosphere. After completion of reaction solventwas evaporated under vacuum to obtain crude product. Water (20 ml) wasadded to the crude product and extracted with dichloromethane (25 ml×3).Combined organic layer was dried over sodium sulphate and evaporatedunder vacuum to obtain crude white solid. It was then purified by columnchromatography using CHCl₃:MeOH; 90:10) as a mobile phase to obtaintitle compound as white solid compound. Yield: 180 mg, (66%), Mass:749.1 (M+H)⁺ M.P. 200-202° C.

Example-174 Compound of Formula I-e where Het is(4,5)-dihydro-1H-imidazol-2-yl

Step A: To a mixture of Example 6 (1.0 g, 1.3 mmol) and ethylene diamine(3.0 ml) was added sulphur powder (21 mg, 0.66 mmol) and heated theresulting reaction mixture at 120° C. for 45 min. Reaction mixture wascooled to room temperature and ice cold water was added under stirring.Crude solid separated was filtered and dried. It was purified by usingcolumn chromatography (15% Acetone-n-Hexane) affording (0.8 gm) paleyellow solid.

Step B: The intermediate from step A (0.75 g, 0.94 mmol) was dissolvedin dichloromethane (60 ml). To this reaction mixture a solutionDess-Martin periodinane (15% in DCM, 3.2 ml, 1.13 mmol) was added underan inert atmosphere. The reaction mixture was stirred at roomtemperature for 15 min. and a solution of Na₂S₂O₃ (10% in saturatedaqueous solution of sodium bicarbonate, 60 ml) was added and stirred for10 min. The organic layer was separated and the aqueous layer wasextracted with dichloromethane (3×15 ml) and the combine organic layerwas dried (Na₂SO₄). The removal of the solvent under reduced pressureprovided the crude solid, which was purified by column chromatographyover silica gel using n-hexane:EtOAc (8:2) as an eluent. The titlecompound was obtained a white solid (0.35 g). m\z ([MH]⁺)=794.

Step C: To the solution of intermediate from step B (0.30 g, 0.37 mmol)in anhydrous THF (25 ml) was added 70% hydrogen fluoride in pyridine (16μl, 0.56 mmol). The reaction mixture was stirred at an ambienttemperature under inert atmosphere for 3 h. To the reaction mixturewater (15 ml) was added and extracted with ethyl acetate (3×15 ml). Thecombined organic layer was dried (Na₂SO₄) and evaporated under reducedpressure. The thick liquid on trituration with n-pentane furnished thetitle compound as a white solid. Yield: 0.18 g (70%), Mass: 681.1(M+H)⁺, M.P.: 152-154° C.

Example 175 Compound of Formula I-e where Het is1-(2-methoxyethoxy)-1H-tetrazol-5-yl Example 176 Compound of Formula I-ewhere Het is 2-(2-methoxyethoxy)-2H-tetrazol-5-yl

Step-1: To the stirring solution of the product obtained in Step B, ofabove Example 12 (2 gm, 1.73 mmol) in acetonitrile (10 ml), 2N HCl (10ml) was added and stirred reaction mixture at room temperature for 4-5hours. Reaction mixture was neutralized with saturated sodiumbicarbonate (20 ml) solution and then extracted in chloroform (2×20 ml).The combined organic layer was washed with water, dried over Na₂SO₄, andthen concentrated it under reduced pressure to get the intermediate II.Yield 1.4 gm.

Step-2: To the stirring solution of compound-II (1.4 gm, 1.82 mmol) inacetone (20 ml) acetic anhydride (0.56 ml, 5.6 mmol) and K₂CO₃ (0.400gm, 2.9 mmol) was added. The reaction mixture was stirred for 24 hoursat room temperature. The solvent was removed under vacuo and water wasadded. It was extracted in chloroform (2×25 ml). The combined organiclayer was washed with water and dried over Na₂SO₄ and evaporated underreduced pressure to yield crude solid compound III. Yield: 1.35 gm

Step-3: To the stirring solution of compound-III (1.35 gm, 1.66 mmol))in dichloromethane (20 ml) was added into 15% Dess-Martin periodinanereagent solution in DCM (5.6 ml, 2 mmol) and stirred it at roomtemperature under nitrogen for 30 minutes. The reaction mixture wasdiluted with 20 ml (1:1) 10% Sodium thiosulphate and sat. sodiumbicarbonate solution. The organic layer was separated and washed withwater and then dried it over Na₂SO₄. and evaporated under reducedpressure to obtain compound IV which was purified by columnchromatography (15% Acetone-Hexane). Yield: 1.3 gm.

Step-4: Compound-IV (1.3 gm, 1.60 mmol) was stirred in methanol (25 ml)for 4-5 hours at room temperature. It was concentrated. It was a mixtureof two regio isomers. It was then separated by using preparative HPLC(Ammonium acetate:acetonitrile). Yield: Isomer-A: 160 mg Mass: m/z:781.1 (M+H). M.P. 112-114° C., Isomer-B: 190 mg, Mass: m/z: 781.1 (M+H),M. P. 122-123° C.

Example 177 Compound of Formula I-e where Het is1-(allyl)-1H-tetrazol-5-yl Example 178 Compound of Formula I-e where Hetis 2-(allyl)-2H-tetrazol-5-yl

Using the above procedure the title compounds were prepared Isomer A:Mass: m/z: 721.1 (M+H), M. P. 130-132° C. Isomer B: Mass: m/z: 721.1(M+H), M. P. 170-172° C.

Example-179 Compound of Formula I-f where T is CH₂CH═CH₂

Step A: To the stirring solution of the Example 7 (15.52 mmol) inacetone was added K₂CO₃ (1.2 eq), allyl bromide (1.1 eq) and refluxed itfor 48 hours. The reaction mixture was concentrated under vacuo. Waterwas added and filtered the residue. Dried it and purified it with columnchromatography (EA; Hexane 24:76). Yield 70%.

Step B: To the stirring solution of the compound obtained in step A(16.6 mmol) in dry DCM was added Dess-Martin periodinane (15% solutionin DCM) (1.2 eq) under N₂ atmosphere for 30 min. The reaction mixturewas diluted with 1:1 10% sodiumthiosulphate solution and saturatedsodium bicarbonate solution. The organic layer was separated and washedwith water and brine; it was dried over Na₂SO₄ and concentrated undervacuo. The residue was purified with column chromatography(Ethylacetate:Hexane 20:80) to afford title compound, yield 50%.

Step C: To the stirring solution of the compound obtained in step B(0.48 mmol) in dry acetonitrile was added 70% HF in Pyridine complex(3.5 eq) The resulting mixture was stirred for 16 hours at roomtemperature under nitrogen atmosphere. The reaction mixture evaporatedunder vacuo. Water was added and extracted it in chloroform. Dried itover Na₂SO₄ and concentrated it. The residue was crystallized fromethanol:water (30:70) to give the title compound in yield 70%. MS 710(M+H)⁺.

Example-180 Compound of Formula I-f where T isCH₂-(5-methyl[1,2,4]oxadiazol-3-yl)

Step A: To a stirred solution of Example 7 (1.0 g, 1.3 mmol) in (10 ml)1,4-dioxan was added (2 ml) N,N-dimethylformamide dimethylacetal andheated at 70° C. for 3 h. After completion of reaction solvent wasevaporated under vacuum, water (30 ml) was added to the crude reactionmass and extracted with ethyl acetate (50 ml×3). Combined organic layerwas dried over anhydrous sodium sulphate and then evaporated yieldingcrude solid. It was then purified by column chromatography using (EthylAcetate:n-hexane; 35:65) as a mobile phase. Pale solid was isolated.Yield: 480 mg, (48%).

Step B: To a stirred solution of the compound obtained in step A (480mg, 0.6 mmol) in dichloromethane (10 ml) was added Dess MartinPeriodinane reagent (2.0 ml, 1.2 equi., 15% solution) under N₂atmosphere at room temperature for 30 min. After completion of reaction,additional 25 ml of dichloromethane was added and then quenched with 30ml saturated aqueous solution of sodium thiosulphate:sodium bicarbonate.Organic layer was dried over anhydrous sodium sulphate and thendistilled off under vacuum to obtain pale yellow solid. It was thenpurified by column chromatography using (Ethyl Acetate:n-Hexane; 30:70)as a mobile phase. Crystalline solid was isolated. Yield: 250 mg, (52%).

Step C: The compound obtained in step B (250 mg, 0.30 mmol) wasdissolved in acetonitrile (10 ml). 70% HF-Pyridine solution (18 μl, 2.0eq.) was added to the above solution and stirred at room temperature forovernight under N₂ atmosphere. After completion of reaction solvent wasevaporated under vacuum to obtain crude product. Water (20 ml) was addedto the crude product and extracted with dichloromethane (25 ml×3).Combined organic layer was dried over sodium sulphate and evaporatedunder vacuum to obtain crude white solid. It was then purified by columnchromatography using CHCl₃:MeOH; 90:10) as a mobile phase to obtaintitle compound as white solid compound. Yield: 120 mg, (56%) MS 694(M+H)⁺.

Example-181 Compound of Formula I-f where T is CO(CH₂)₂-(3-fluorophenyl)

Step-1: To the stirred solution of 3-(3-fluoro-phenyl)-propionic acid(0.321 g, 1.91 mmol) in dichloromethane (10 ml) was addeddicyclohexylcarbodiimide (0.788 g, 3.82 mmol) followed by1-hydroxy-benzotriazole (HOBT) (0.129 g, 0.955 mmol) at a temperaturebetween 25-30° C. The reaction mixture was stirred for 30 minutes. Tothe reaction mixture was added Example-7 (1.0 g, 1.3 mmol) followed byN,N-dimethylamino pyridine (0.077 g, 0.636 mmol) under stirring and itwas stirred for additional 1 hour at 25-30° C. temperature. Theresultant mixture was filtered under suction, the filtrate wasevaporated under vacuum to provide step-1 product as a thick liquid in0.91 g quantity, which was used without purification for furtherreaction MS: m/z: 936.1 (M+1).

Step-2: To the stirred solution of N-chlorosuccinimide (0.97 g, 7.28mmol) in dichloromethane (15 ml) at 0° C. was added dimethyl sulfide(1.6 ml, 12.12 mmol). The mixture was stirred at 0° C. for additionalfor 30 minutes. The reaction mixture was cooled to −40° C. and thesolution of step-1 product (0.91 g, 0.97 mmol) dissolved indichloromethane (10 ml) was added. The resulting reaction mixture wasstirred at −40° C. temperature for 2 hr and then allowed to warm at25-30° C. while stirring. Triethyl amine (0.980 ml, 9.71 mmol) was addedto the reaction mixture at 25-30° C. and it was stirred for additional30 minutes. The reaction mixture was quenched by pouring in aqueoussaturated sodium bicarbonate solution and was extracted withdichloromethane (3×25 ml). The combined separated organic layer wasdried over Na₂SO₄ and was evaporated to provide residue. The residue waspurified by using silica gel column chromatography (10% acetone:hexanes)to provide step-2 product as a off white solid in 80.3% (0.73 g) yield.MS: m/z: 934.1 (M+1).

Step-3: Deprotection: To a mixture of step-2 compound (0.73 g, 0.782mmol) and 70% HF-pyridine solution (26 μl, 0.912 mmol) in acetonitrile(10 ml), was added at 25-30° C. temperature for 2 hr. The solvent wasevaporated under vacuum to obtain a crude residue. To the crude residue,water (20 ml) was added and the mixture was extracted withdichloromethane (3×25 ml). Combined organic layer was dried over Na₂SO₄and evaporated under vacuum to obtain crude solid. The crude solid waspurified by using silica gel column chromatography (CHCl₃:MeOH; 90:10)to obtain title compound as white solid compound in 78.3% (0.570 g)yield. Mp: 174-177° C., MS: m/z: 820.1 (M+1).

Following examples were prepared by using above procedure and by usingcarboxylic acid A.

Mp Mass Example T Carboxylic acid (A) (° C.) (M + 1) 182CO(CH₂)₂-(3-(3-fluoro 3-[3-(3-fluoro-phenyl)- 166-168 888.1phenyl)-[1,2,4]oxadiazol-5- [1,2,4]oxadiazol-5-yl]- yl) propionic acid183 CO(CH₂)₂-(3,4-dimethoxy 3-(3,4-dimethoxy- 168-170 862.1 phenyl)phenyl)-propionic acid 184 CO(CH₂)₂-(4-methoxy 3-(4-methoxy-phenyl)-154-160 803.1 phenyl) propionic acid

Example-185 Compound of Formula I-f where T is CH₂C≡CH

Step-A: To the stirred solution of Example-7 (1.0 g, 1.3 mmol) intoluene (15 ml) was added potassium tert-butoxide (0.16 g, 1.43 mmol)and 18-crown-6-ether (0.048 g, 0.13 mmol) at 25-30° C. temperature. Thereaction mixture was stirred for 10 min at 25-30° C. temperature.3-bromo-propyne (127 μl, 1.43 mmol) was added to the reaction mixtureand it was stirred for additional 1 hour. It was quenched by pouring itin aqueous saturated ammonium chloride solution (20 ml). The mixture wasextracted with ethyl acetate (3×25 ml). Combined organic layer was driedover Na₂SO₄ and purified by using silica gel column chromatography (10%acetone:Hexane) to provide step-1 product as a pale yellow solid in 74%(0.77 g) yield. MS: m/z 825 (M+1).

Step-B: To the stirred solution of N-chlorosuccinimide (0.94 g, 7.0mmol) in dichloromethane (20 ml) at 0° C. was added dimethyl sulfide(0.86 ml, 11.8 mmol). The reaction mixture was then stirred at 0° C. for30 min. The step-1 product (0.77 g, 0.94 mmol) dissolved indichloromethane (10 ml) was added to the reaction mixture at −40° C. Theresulting reaction mixture was stirred at the 0° C. temperature for 2 hrand allowed to warm at 25-30° C. temperature under stirring. Triethylamine (1.3 ml, 9.4 mmol) was added to the reaction mixture and stirredfor additional 30 min. The mixture was poured in aqueous saturatedsodium bicarbonate solution and extracted with dichloromethane (3×25ml). The combined organic layer was dried over Na₂SO₄ and purified byusing silica gel column chromatography (10% acetone:Hexane) to providestep-2 product as a off white solid in 80% (0.62 g) yield. MS: m/z: 823(M+1).

Step-C: A mixture of step-2 product (0.62 g, 0.75 mmol) and 70%HF-pyridine solution (32 μl, 1.1 mmol) dissolved in acetonitrile (10 ml)was stirred at 25-30° C. for 2 hr. After completion of reaction, solventwas evaporated under vacuum to obtain a residue. Water (20 ml) was addedto the residue and the mixture was extracted with dichloromethane (3×25ml). Combined organic layer was dried over sodium sulphate andevaporated under vacuum to obtain a crude solid. The crude solid waspurified by using silica gel column chromatography (10% MeOH:CHCl₃) toobtain title compound as white solid in 60% (0.37 g) yield. Mp: 202-204°C., MS: m/z: 709.1 (M+1).

Example-186 Compound of Formula I-f where T is CH₂CH≡C-(pyridin-2-yl)

Step-A: To the stirred suspension of Pd(PPh₃)₂Cl₂ (0.13 g, 0.18 mmol),CuI (46 mg, 0.24 mmol) and 2-iodoyridine (0.25 g, 1.2 mol) a solution ofcompound obtained in step A of the above example (1.0 g, 1.2 mmol)dissolved in diethyl amine (5.0 ml) was added at 25-30° C. temperature.The reaction mixture was stirred under inert atmosphere for additional 3hr at 25-30° C. It was poured in ice cold water and extracted with ethylacetate (3×25 ml). Combined organic layer was dried over Na₂SO₄ andevaporated under vacuum to provide a crude mass. The crude mass waspurified by using silica gel column chromatography (15% acetone-Hexane)to yield step-1 product as a pale yellow solid in 60% (0.65 g) yield.MS: m/z: 901 (M+1)

Step-B: To the stirred solution of N-chlorosuccinimide (0.73 g, 5.5mmol) in dichloromethane (20 ml) at 0° C. was added dimethyl sulfide(0.66 ml, 9.1 mmol). The reaction mixture was stirred under inertatmosphere at 0° C. for 30 min. The step-1 product (0.65 g, 0.73 mmol)dissolved in dichloromethane (10 ml) was added to the reaction mixtureat −40° C. The resulting reaction mixture was stirred at the 0° C.temperature for 2 hr and allowed to warm at 25-30° C. temperature.Triethyl amine (1.0 ml, 7.3 mmol) was added to the reaction mixture andstirred for additional 30 min. The reaction mixture was poured inaqueous saturated sodium bicarbonate solution. The separated organiclayer dried over Na₂SO₄ and purified by using silica gel columnchromatography (10% Acetone:Hexane) to obtain step-2 product as a offwhite solid in 75% (0.49 g) yield. MS: m/z: 899 (M+1).

Step-C: A mixture of step-2 product (0.48 g, 0.53 mmol) and 70%HF-pyridine solution (23 μl, 0.8 mmol) dissolved in acetonitrile (10 ml)was stirred at 25-30° C. for 2 hr under N₂ atmosphere. After completionof reaction, solvent was evaporated under vacuum to obtain crude mass.Water (20 ml) was added to the crude mass and the mixture was extractedwith dichloromethane (3×25 ml). Combined organic layer was dried oversodium sulphate and evaporated under vacuum to obtain crude solid. Thecrude solid was purified by using column chromatography (CHCl₃:MeOH;90:10) to obtain title compound as white solid in 70% (0.29 g) yield.MS: m/z: 785 (M+1). Mp: 179-183° C.

Following examples were prepared by using above procedure and by usingreactant A.

Mass Example T Reactant (A) Mp (° C.) (M + 1) 187 CH₂C≡C-(3-cyano)phenyl3-Iodo-benzo nitrile 139-142 809.1 188 CH₂C≡C-(3-fluoro)phenyl1-Fluoro-3-iodo-benzene 175-178 802.1 189 CH₂C≡C-(3-chloro)phenyl1-Chloro-3-iodo-benzene 171-174 818.1 190 CH₂C≡C-(3-methoxy)1-Iodo-3-methoxy- 168-171 814.1 phenyl benzene 191 CH₂C≡C-(2-chloro2-Chloro-5-iodo-pyridine 167-170 819.1 pyridin-5-yl) 192CH₂C≡C-(2-fluoro pyridin- 2-Fluoro-5-iodo-pyridine 173-176 803.1 5-yl)193 CH₂C≡C-(pyridin-3-yl) 3-Iodo-pyridine 132-137 785.1

Example-194 Compound of Formula I-f where T is CH₂-phenyl

Step-1: To the solution of Example-7 (1.0 g, 1.3 mmol) in toluene (10ml) was added potassium tert-butoxide (0.160 g, 1.43 mmol),18-crown-6-ether (0.048 g, 0.13 mmol), followed by benzyl bromide (182μl, 1.56 mmol) at a 25-30° C. The reaction mixture was stirred at 25-30°C. temperature for 1 hour. After completion of the reaction, thereaction mixture was poured in saturated aqueous ammonium chloridesolution (20 ml). The mixture was extracted with ethyl acetate (3×25ml). Combined organic layer was dried over Na₂SO₄ and evaporated undervacuum to provide a residue. The residue was purified by using silicagel column chromatography (10% acetone:hexanes) to provide step-1product as a off white solid in 76.2% (0.85 g) yield. MS: m/z: 876 (M+1)

Step-2: Method A: To the stirred solution of N-chlorosuccinimide (0.97g, 7.28 mmol) in dichloromethane (15 ml) at 0° C. was added dimethylsulfide (1.6 ml, 12.12 mmol). The reaction mixture was stirred at 0° C.for additional 30 minutes. The complex was cooled to −40° C. and thesolution of step-1 product (0.85 g, 0.97 mmol) dissolved indichloromethane (10 ml) was added. The resulting reaction mixture wasstirred at −40° C. temperature for 2 hr and allowed to warm at 25-30° C.under stirring. Triethyl amine (0.980 ml, 9.71 mmol) was added to thereaction mixture at 25-30° C. and was stirred for additional 30 minutes.The mixture was poured in aqueous saturated sodium bicarbonate solution(50 ml) and it was extracted with dichloromethane (3×25 ml). Thecombined organic layer was dried over Na₂SO₄ and was evaporated toprovide a residue. The residue was purified by using silica gel columnchromatography (10% acetone:hexanes) to provide step-2 product as a offwhite solid in 79% (0.67 g) yield. MS: m/z; 874 (M+1).

Method B: Alternatively, oxidation was carried our by using Dess-martinperiodinane reagent as follows: To the stirred solution of the step-1product (1.5 g, 1.6 mmol) in dichloromethane (10 ml), was addedDess-martin periodinane (5.0 ml, 1.76 mmol, 15% solution indichloromethane). The reaction mixture was stirred at a temperature25-30° C. for 30 min. The reaction mixture was poured in 1:1 mixture ofaqueous saturated sodium bicarbonate solution and aqueous saturatedsodium thiosulphate solution and it was extracted with dichloromethane(3×25 ml). The combined organic layer was dried over Na₂SO₄ and purifiedby using silica gel column chromatography (10% Acetone:Hexane) toprovide step-2 product in 46% (0.7 g) yield. MS: m/z; 874 (M+1).

Step-3: To a mixture of step-2 product (0.67 g, 0.76 mmol) and 70%HF-pyridine solution (26 μl, 0.912 mmol) in acetonitrile (10 ml), wasstirred at 25-30° C. temperature for 2 hr. The solvent was evaporatedunder vacuum to obtain a crude residue. To the crude residue, water (20ml) was added and the mixture was extracted with dichloromethane (3×25).Combined organic layer was dried over Na₂SO₄ and evaporated under vacuumto obtain a crude solid. The crude solid was purified by using silicagel column chromatography (CHCl₃:MeOH; 90:10) to afford title compoundas white solid compound in 76.2% (0.51 g) yield. MS: m/z: 761.1 (M+1).Mp: 200-204° C.

Following examples were prepared by using above procedure and by usingreactant A.

Mass Example T Reactant (A) Mp (° C.) (M + 1) 195 CH₂-(4-methoxyphenyl)1-bromomethyl-4- 184-187 790.1 methoxy-benzene 196 CH₂-(3-chlorophenyl)1-bromomethyl-3-chloro- 212-214 794.1. benzene 197 CH₂-(3-methoxyphenyl)1-bromomethyl-3- 212-215 790.1 methoxy-benzene 198 CH₂-(4-(1H-[1,2,4]1-(4-bromo methylphe- 150-154 827.1 triazol)phenyl)yl)-1H-[1,2,4]triazole 199 CH₂-(4-(isopropyl)phenyl) 1-Bromomethyl-4-189-191 802.1 isopropyl-benzene 200 CH₂-(2-fluorophenyl1-Bromomethyl-2-fluoro- 176-179 778.1 benzene 201CH₂-(4-(pyrimidin-5-yl) 5-(4-bromo methyl- 164-167 838.1 phenyl)phenyl)-pyrimidine 202 CH₂-(4-(pyridin-2-yl) 2-(4-bromo methyl- 170-172837.1 phenyl) phenyl)-pyridine 203 CH₂C(═CH₂)CH₃ 3-Chloro-2-methyl-174-177 714.1 propene 204 CH₂CH═CHCH₃ 1-Chloro-but-2-ene 221-224 724.1205 CH₂CH═C(CH₃)₂ 1-Chloro-3-methyl-but-2- 244-248 738.1 ene 206CH₂C(F)═CH₂ 3-Chloro-2-fluoro-1- 174-176 728.1 propene

Example-207 Compound of Formula I-f where T is CH₂CH═CH-(pyridin-3-yl)

Step A: To the stirring solution of Step A product from Example 179 (1.5g, 1.81 mmol) in DMF (15 ml) was added sodium acetate (0.24 g, 2.73mmol). To the above solution Tetrakis triphenyl phosphine palladium (0)(0.21 g, 0.18 mmol) and 3-bromopyridine (0.195 μl, 1.99 mmol) were addedand stirred the reaction mixture for 12 hour at 120° C. temperature. Thereaction mixture was then poured in sat. ammonium chloride solution (20ml) and extracted with ethyl acetate (50 ml×3). Combined organic layerwas dried over Na₂SO₄ it was then purified over silica gel columnchromatography (18% Acetone:Hexane), yield (0.65 g, 53%).

Step B: To the stirred solution of step-1 compound (0.65 g, 0.72 mmol)in DCM (130 ml) was added Dess-Martin perriodinane reagent (15% solutionin DCM) (3.4 ml, 1.18 mmol) at 25-30° C. temperature. The reactionmixture was stirred further for 30 min. The reaction mixture wasquenched with 1:1 mixture of aqueous saturated sodium bicarbonatesolution and aqueous sodium thiosulfate solution (2×200 ml) the organiclayer was washed with brine (100 ml). Combined organic layer was driedover Na₂SO₄ and concentrated under vacuum to provide a crude mass. Thecrude material was purified by flash column chromatography usingacetone:hexane 2.2:7.8 mixture to provide pale yellow solid in 45% (0.35g) yield.

Step C: To the solution of compound obtained from above step (0.35 g,0.37 mmol) in acetonitrile (15 ml) was added 70% hydrogen fluoride inpyridine (16 μl, 0.58 mmol) under inert atmosphere and stirred for 3 h.The residue obtained after evaporation of solvent under reduced pressurewas dissolved in ethyl acetate (15 ml) and washed with water (2×10 ml).The organic layer was dried over Na₂SO₄ and evaporated under reducedpressure to provide crude solid which on trituration in diethyl etherafforded white solid as the title compound. Yield: 0.180 g (60%), Mass:m/z: 787.1 (M+H), Mp: 212-215° C.

Following examples were prepared by using above procedure and by usingreactant A.

Ex- Mp Mass ample T Reactant (A) (° C.) (M + 1) 208 CH₂CH═CH-iodobenzene 202- 786.1 phenyl 205 209 CH₂CH═CH-(4- 1-iodo-4-trifluoro 96- 854.1 trifluoromethyl) methyl-benzene 100 phenyl 210CH₂CH═CH-(3-tri- 1-iodo-3-trifluoro 206- 854.1 fluoromethyl)phenylmethyl-benzene 210 211 CH₂CH═CH-(3- 1-fluoro-3-iodo-benzene 214- 804.1fluoro)phenyl 216 212 CH₂CH═CH-(3- 1-chloro-3-iodo-benzene 154- 820.1chloro)phenyl 158 213 CH₂CH═CH— 5-Iodo-pyrimidine 158- 788.1(pyrimidin-5-yl) 160

Example-214 Compound of Formula I-f where T is CH₂CONH-(3-chlorophenyl)

Step-1: To the stirred solution of m-chloro aniline (2.0 g, 1.57 mmol)in THF (20 ml) was added triethyl amine (2.62 ml, 1.88 mmol),bromoacetyl bromide (1.51 ml, 1.73 mmol) at 5° C. and the reactionmixture was stirred for 1 hour at 25-30° C. temperature. The reactionmixture was poured in aqueous saturated ammonium chloride solution (20ml) and extracted with ethyl acetate (3×25 ml). Combined organic layerdried over Na₂SO₄ and distilled under reduced pressure. Yellow colouredcompound was obtained as a step-1 product and utilized for the nextstep.

Step-2: To the stirred solution of Example-7 (2.00 g, 2.50 mmol) intoluene (10 ml) was added potassium hydride (3.41 g, 0.30 mmol) and18-crown-6-ether (0.08 mg, 0.30 mmol) at 25-30° C. temperature. Thereaction mixture was stirred for additional 10 min. and step-1 product2-bromo-N-(3-chloro-phenyl)-acetamide (0.69 g, 2.81 mmol) was added. Thereaction mixture was stirred for 1 hour at 25-30° C. temperature. It waspoured in aqueous saturated ammonium chloride solution (30 ml) andextracted with ethyl acetate (3×25 ml). Combined organic layer was driedover Na₂SO₄ and purified by using silica gel column chromatography (10%Acetone:Hexane) to provide step-2 product as a off white solid in 70%(1.68 g) yield. MS: m/z: 953 (M+1).

Step-3: To the stirred solution of N-chlorosuccinimide (1.77 gm, 13.22mmol) in dichloromethane (20 ml) at 0° C. was added dimethyl sulfide(1.62 ml, 22.00 mmol). The reaction mixture was stirred at 0° C. fornext 30 min. The Step-1 product (1.68 gm, 1.76 mmol) dissolved indichloromethane (10 ml) was added to the reaction mixture at −40° C. Theresulting reaction mixture was stirred at the same temperature for 2 hrand allowed to warm at 25-30° C. temperature. Triethyl amine (2.45 ml,17.62 mmol) was added to the reaction mixture and stirred for additional30 min. The reaction mixture was poured in aqueous saturated sodiumbicarbonate solution and extracted with dichloromethane (3×25 ml). Thecombined organic layer dried over Na₂SO₄ and purified by using silicagel column chromatography (10% acetone:hexane) to provide step-3 productas a off white solid in 80% (1.34 g) yield. MS: m/z: 951 (M+1).

Step-4: A mixture of step-3 product (1.34 gm, 1.40 mmol) and 70%HF-pyridine solution (60 μl, 2.16 mmol) in acetonitrile (10 ml) wasstirred at 25-30° C. for 2 hr. After completion of reaction, solvent wasevaporated under vacuum to obtain crude mass. Water (20 ml) was added tothe crude mass and extracted with dichloromethane (3×25 ml). Combinedorganic layer was dried over sodium sulphate and evaporated under vacuumto obtain crude solid. The crude solid was purified by using silica gelcolumn chromatography (10% MeOH:CHCl₃) to obtain title compound as whitesolid in 35% (0.42 g) yield. MS: m/z: 838 (M+1). Mp: 183-186° C.

Following examples were prepared by using above procedure and by usingreactant A.

Ex- Mp Mass ample T Reactant (A) (° C.) (M + 1) 215 CH₂CONH-(3-fluoro-2-bromo-N-(3- 176-178 821.1 phenyl) fluoro- phenyl)-acetamide 216CH₂CO-(4-phenyl- 2-bromo-1-(4- 214-218 872.1 piperazin-1-yl) phenyl-piperazin-1-yl- ethanone 217 CH₂CONH₂ 2-bromoacetamide 220-222 727.1 218CH₂CON(CH₃)₂ 2-bromo-N,N- 210-214 755.1 dimethylacetamide 219CH₂CONH-(cyclo- 2-bromo-N-cyclo- 214-218 767.1 propyl) propyl-lacetamide

Example-220 Compound of Formula I-f where T isCH₂-(5-(pyridin-3-yl)[1,3,4]oxadiazol-2-yl)

Step-1: To a mixture of 3-cyanopyridine (12 g, 115 mmol) andtrimethylsilyl azide (20 ml, 150 mmol), was added a solution of 0.1 Mtetra-n-butylammonium fluoride in THF (57 ml, 56 mmol) at 25-30° C.temperature. The resulting mixture was heated at 80° C. for overnight.The mixture is allowed to warm at 25-30° C. temperature and thenquenched in ice-water mixture. Solid precipitated out was filtered andwashed with water (2×25 ml) and dried under vacuum to provide step-1compound in 62% (10.5 g) yield. MS: 148 (M+1).

Step-2: To the stirred solution of 3-(1H-tetrazol-5-yl)-pyridine (10.5g, 71.42 mmol) in toluene (50 ml) was added chloroacetic anhydride (25g, 92.80 mmol) and resulting mixture was heated at 100° C. for 2-3hours. The reaction mixture was allowed to warm at 25-30° C.temperature. The mixture was quenched with saturated aqueous sodiumbicarbonate solution (500 ml) and extracted with chloroform (2×200 ml).The combined organic layer was washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure to provide a crude mass. The crudemass was purified over silica gel column chromatography to provide titlecompound in 56% (7.8 g) yield. MS: 196 (M+1).

Step-3: To the stirred solution of potassium hydride (5.5 g, 41 mmol)and 18-crown-6 (1.1 g, 4.1 mmol) in toluene (200 ml) was added Example-7(25 g, 32 mmol). It was allowed to stir at 25-30° C. temperature for 30min. (5-chloromethyl-1,3,4-oxadiazole-2-yl)-pyridine (7.8 g, 38 mmol)was added to the reaction mixture. The reaction mixture was stirred at25-30° C. temperature for 30 minutes. It was quenched with aqueoussaturated ammonium chloride solution (500 ml). The organic layer waswashed with brine (500 ml), dried over Na₂SO₄ and concentrated undervacuum to provide a crude mass. The crude mass was purified by flashcolumn chromatography (acetone:hexane 2.5:7.5) to provide off whitesolid in 43% (13 g) yield. MS: m/z 945 (M+1).

Step-4: To the stirred solution of step-3 compound (13 g, 14 mmol) inDCM (130 ml) was added Dess-Martin periodinane reagent (15% solution inDCM) (58 ml, 21 mmol) at 25-30° C. temperature. The reaction mixture wasstirred further for 30 min. The reaction mixture was quenched with 1:1mixture of aqueous saturated sodium bicarbonate solution and aqueoussodium thiosulfate solution (2×200 ml) the organic layer was washed withbrine (100 ml). Combined organic layer was dried over Na₂SO₄ andconcentrated under vacuum to provide a crude mass. The crude materialwas purified by flash column chromatography using acetone:hexane 2.2:7.8mixture to provide pale yellow solid in 45% (7.4 g) yield. MS: m/z: 943(M+1).

Step-5: A mixture of step-4 compound (7.4 g, 7.8 mmol) in acetonitrile(74 ml) and 70% HF-pyridine complex (0.3 ml, 12 mmol) was stirred at25-30° C. temperature for 3-4 hours. The reaction mixture wasconcentrated under reduced pressure and water was added and the mixturewas extracted with DCM (2×40 ml). Combined organic layer was dried overNa₂SO₄ and concentrated under vacuum. The crude mass was purified byflash column chromatography (MeOH:CHCl₃ 1.2:8.8) to give title compoundas a white solid in 45% (3.4 g) yield. MS: m/z: 829 (M+1). Mp: 212-214°C.

Following examples were prepared by using above procedure and by usingreagent A.

Example T Reagent A Mp (° C.) Mass (M + 1) 221 CH₂-(5-phenyl[1,3,4]2-chloromethyl-5-phenyl 134-136 829.1 oxadiazol-2-yl) [1,3,4]-oxadiazole222 CH₂-(5-(3-fluorophenyl) 2-chloromethyl-5-(3- 125-127 845.1[1,3,4]oxadiazol-2-yl) fluoro-phenyl)-[1,3,4]- oxadiazole 223CH₂-(5-(4-methoxy phen- 2-chloromethyl-5-(4- 130-133 857.1yl)[1,3,4]oxadiazol-2-yl) methoxy-phenyl)-[1,3,4]- oxadiazole 224CH₂-(5-(pyridin-2-yl) 2-(5-chloromethyl- 205-208 829.1[1,3,4]oxadiazol-2-yl) [1,3,4]-oxadiazol- 2-yl)-pyridine 225CH₂-(5-(pyrazin-2- 2-(5-chloromethyl- 188-190 831.1yl)[1,3,4]oxadiazol-2-yl) [1,34,]-oxadiazol- 2-yl)-pyrazine 226CH₂-(5-(3,5-dimethoxy 2-chloromethyl-5-(3,5- 171-179 887.1phenyl)[1,3,4]oxadiazol- dimethoxy-phenyl)- 2-yl) [1,3,4]-oxadiazole 227CH₂-(5-(pyrimidin-2- 2-(5-chloromethyl- 187-191 831.1yl)[1,3,4]oxadiazol-2-yl) [1,3,4]-oxadiazol- 2-yl)-pyrimidine 228CH₂-((5-cyclopropyl)- 2-chloromethyl-5- 186-192 791.1[1,3,4]oxadiazol-2-yl) cyclopropyl-[1,3,4]- oxadiazole 229CH₂-(5-(6-methoxy- 2-(5-chloromethyl- 225-230 860.1 pyridin-2-yl)[1,3,4][1,3,4]-oxadiazol- oxadiazol-2-yl) 2-yl)-6-methoxy-pyridine 230CH₂-(5-(5-methyl-pyri- 2-(5-chloromethyl- — 844.1 din-2-yl)[1,3,4][1,3,4]-oxadiazol-2-yl)- oxadiazol-2-yl) 5-methyl-pyridine 231CH₂-(5-(5-cyclopropyl- 2-(5-chloromethyl-[1,3,4]- — 870.1pyridin-2-yl)[1,3,4] oxadiazol-2-yl)-5- oxadiazol-2-yl)cyclopropyl-pyridine 232 CH₂-(5-(5-cyano-pyridin-2-(5-chloromethyl-[1,3,4]- — 855.1 2-yl)[1,3,4]oxadiazol-2-oxadiazol-2-yl)-5- yl) cyano-pyridine 234 CH₂-(5-(5-dimethyl2-(5-chloromethyl-[1,3,4]- — 874.1 amino-pyridin-2-yl)oxadiazol-2-yl)-5- [1,3,4]oxadiazol-2-yl) dimethyl amino-pyridine 235CH₂-(5-(5-methoxy- 2-(5-chloromethyl-[1,3,4]- — 860.1pyridin-2-yl)[1,3,4] oxadiazol-2-yl)-5- oxadiazol-2-yl) methoxy-pyridine236 CH₂-(5-(5-fluoro-pyridin- 2-(5-chloromethyl-[1,3,4]- — 848.12-yl)[1,3,4]oxadiazol-2- oxadiazol-2-yl)-5- yl) fluoro-pyridine 237CH₂-(5-(5-chloro-pyridin- 2-(5-chloromethyl- — 864.12-yl)[1,3,4]oxadiazol-2- [1,3,4]-oxadiazol-2- yl) yl)-5-chloro-pyridine238 CH₂-(5-(pyrimidin-5- 5-(5-chloromethyl-[1,3,4]- — 831.1yl[1,3,4]oxadiazol-2-yl) oxadiazol-2-yl)- pyrimidine

Example-239 Compound of Formula I-f, where T isCH₂-(3-(pyridin-2-yl)[1,2,4]oxadiazol-5-yl)

Step-1: To the stirred suspension of hydroxylamine hydrochloride (8.01g, 120 mmol) in methanol (100 ml) was added sodium bicarbonate (10.50 g,130 mmol) followed by pyridine-2-carbonitrile (10 g, 96 mmol). Thereaction mixture was refluxed for 2 hours. The solvent was removed undervacuum to provide a residue. Water (200 ml) was added to the residue.The solid separated was filtered under suction and washed with water(100 ml) dried under vacuum to provide step-1 product as a white solidin 93% (12.5 g) yield. MS: m/z: 138 (M+1).

Step-2: To the stirred suspension of step-1 product (12.50 g, 91.2 mmol)in acetone (100 ml), chloroacetyl chloride (7.36 ml, 120 mmol) was addeddrop-wise at 25-30° C. temperature. The reaction mixture was stirred for30 minutes. The solid separated was filtered and stirred with saturatedaqueous NaHCO₃ solution (200 ml). The suspension was filtered and washedwith water, dried under vacuum to provide step-2 product as a off whitesolid in 83% (18 g) yield. The solid was used as it is for the nextstep. MS: m/z: 214.6 (M+1).

Step-3: The step-2 product (18 g, 85 mmol) was refluxed in toluene (200ml) along with 4 Å molecular sieves for 2 hrs. The reaction mixture wasconcentrated under vacuum to provide a crude residue. The crude residuewas triturated with diethyl ether to afford5-chloromethyl-1,2,4-oxadiazol-3-yl)-pyridine, as step-3 product as aoff white solid in 96% (16 g) yield. MS: m/z: 197.6 (M+1).

Step-4: To the stirred mixture of potassium hydride (2.1 g, 17 mmol),18-crown-6 (0.33 g, 1.2 mmol) in toluene (100 ml) was added Example-7(10 g, 13 mmol). The reaction mixture was stirred at 25-30° C.temperature for 30 min and step-3 product,2-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-pyridine (3.2 g, 14 mmol)dissolved in toluene (5 ml) was added to the reaction mixture. It wasstirred for additional 30 min. The reaction mixture was quenched byaddition of saturated aqueous ammonium chloride solution (250 ml).Layers were separated. The organic layer was washed with brine (250 ml),dried over Na₂SO₄, concentrated under vacuum to provide crude solid. Thecrude solid was purified by flash column chromatography (acetone:hexane2.5:7.5) to isolate step-4 product as a off white solid in 58% (7.0 g)yield. MS: m/z: 945 (M+1).

Step-5: To a stirred solution of N-chlorosuccinimide (8.66 g, 56 mmol)in dry toluene (100 ml) at 0° C. was added dimethyl sulfide (7.7 ml, 93mmol). A white precipitate appeared. The mixture was cooled to −40° C.,and a solution of step-4 product (7.0 g, 7.4 mmol) in DCM (30 ml) wasadded over 30 min. Stirring was continued for 3 hours at sametemperature. TEA (12.5 ml, 74 mmol) was added to the reaction mixtureand the reaction mixture was allowed warm at 25-30° C. temperature. Itwas quenched with saturated aqueous sodium bicarbonate solution (100ml). The organic layer was washed with brine (100 ml), dried over Na₂SO₄concentrated under vacuum to provide a crude mass. The crude mass waspurified by using silica gel column chromatography (acetone:Hexane;20:80) to isolate step-5 product as a off white solid in 67% (4.7 g)yield. MS: m/z: 943 (M+1).

Step-6: A mixture of the step-5 product (4.7 g, 5.0 mmol) and 70%HF-Pyridine complex (0.17 ml, 7.5 mmol) in acetonitrile (40 ml) wasstirred at 25-30° C. temperature for 3-4 hours. The reaction mixture wasconcentrated under vacuum to provide a residue and to the residue, water(50 ml) was added. The product was extracted in DCM (2×30 ml), driedover Na₂SO₄ and concentrated under vacuum to provide a crude solid. Thecrude solid was purified by using flash column chromatography(MeOH:CHCl₃; 1.5:8.5) to give title compound in 61% (2.5 g) yield. MS:m/z: 829 (M+1) Mp: 172-175° C.

Following examples were prepared by using above procedure and by usingReagent A in the place of2-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-pyridine.

Example T Reagent (A) Mp (° C.) Mass (M + 1) 240 CH₂(3-phenyl[1,2,4]5-chloromethyl-3-phen- 162-165 827.1 oxadiazol-5-yl)yl-[1,2,4]-oxadiazole 241 CH₂-(3-(3-fluorophenyl)5-chloromethyl-3-fluoro 150-152 845.1 [1,2,4]oxadiazol-5-yl)phenyl-[1,2,4]- oxadiazole 242 CH₂-(3-(3-chlorophen5-chloromethyl-3-chloro 154-157 861.1 yl)[1,2,4]oxadiazol-5-yl)phenyl-[1,2,4]oxadiazole 243 CH₂-(3-(4-methoxyphen5-chloromethyl-4-methoxy- 173-176 857.1 yl)[1,2,4]oxadiazol-5-yl)phenyl-[1,2,4] oxadiazole 244 CH₂-(3-(pyridin-3-yl)3-(5-chloromethyl-[1,2,4] 210-214 829.1 [1,2,4]oxadiazol-5-yl)oxadiazol-3-yl)-pyridine 245 CH₂-(3-(4-chlorophenyl) 5-chloromethyl-4-135-138 861.1 [1,2,4]oxadiazol-5-yl) chlorophenyl-[1,2,4] oxadiazole 246CH₂-(3-(3,5-dimethoxy 5-chloromethyl-3,5- 154-158 887.1phenyl)[1,2,4]oxadiazol- dimethoxy phenyl-[1,2,4] 5-yl) oxadiazole 247CH₂-(3-(pyrimidin-2- 2-(5-chloromethyl-[1,2,4] 162-165 831.1yl)[1,2,4]oxadiazol-5-yl) oxadiazol-3-yl)- pyrimidine 248CH₂-(3-cyclopropyl 5-chloromethyl-3-cyclo 176-178 792.1[1,2,4]oxadiazol-5-yl) propyl-[1,2,4]oxadiazole 249 CH₂-(3-(6-methyl2-(5-chloromethyl-[1,2,4] 202-205 842.1 pyridin-2-yl)[1,2,4]oxadiazol-3-yl)-6- oxadiazol-5-yl) methyl-pyridine 250 CH₂-(3-(3-methyl2-(5-chloromethyl-[1,2,4] 194-198 842.1 pyridin-2-yl)[1,2,4]oxadiazol-3-yl)-3- oxadiazol-5-yl) methyl-pyridine 251 CH₂-(3-(5-methyl-2-(5-chloromethyl- — 844.1 pyridin-2-yl)[1,2,4] [1,2,4]-oxadiazol-oxadiazol-5-yl) 3-yl)-5-methyl-pyridine 252 CH₂-(3-(5-cyclopropyl-2-(5-chloromethyl- — 870.1 pyridin-2-yl)[1,2,4] [1,2,4]-oxadiazol-oxadiazol-5-yl) 3-yl)-5-cyclo propyl- pyridine 253CH₂-(3-(5-cyano-pyridin- 2-(5-chloromethyl- — 855.12-yl)[1,2,4]oxadiazol-5- [1,2,4]-oxadiazol- yl) 3-yl)-5-cyano-pyridine254 CH₂-(3-(5-dimethyl 2-(5-chloromethyl- — 874.1 amino-pyridin-2-yl)[1,2,4]-oxadiazol- [1,2,4]oxadiazol-5-yl) 3-yl)-5-dimethyl amino-pyridine 255 CH₂-(3-(5-methoxy- 2-(5-chloromethyl- — 860.1pyridin-2-yl)[1,2,4] [1,2,4]-oxadiazol- oxadiazol-5-yl)3-yl)-5-methoxy-pyridine 256 CH₂-(3-(5-fluoro- 2-(5-chloromethyl- —848.1 pyridin-2-yl)[1,2,4] [1,2,4]-oxadiazol- oxadiazol-5-yl)3-yl)-5-fluoro-pyridine 257 CH₂-(3-(5-chloro- 2-(5-chloromethyl- — 864.1pyridin-2-yl)[1,2,4] [1,2,4]-oxadiazol- oxadiazol-5-yl)3-yl)-5-chloro-pyridine 258 CH₂-(3-(pyrimidine-5- 5-(5-chloromethyl- —831.1 yl)[1,2,4]oxadiazol-5-yl) [1,2,4]-oxadiazol- 3-yl)-pyrimidine

Example-259 Compound of Formula I-f where T isCH₂-(5-(pyridin-3-yl)[1,2,4]oxadiazol-3-yl)

Step-1: To the stirred solution of 2-chloroacetamidoxime (1.0 g, 9.2mmol, prepared as per the procedure given in PCT/US02/22897) in toluene(15 ml) was added nicotinyl chloride (1.37 g, 9.67 mmol) and heated at110° C. for 4 hr. The reaction mixture was diluted with ethyl acetate(50 ml) and washed with aqueous saturated sodium bicarbonate solution(2×25). Organic layer was evaporated under vacuum to yield the crudeproduct. The crude product was purified using silica gel columnchromatography (15% Acetone-Hexane) to give2-(3-chloromethyl-[1,2,4]-oxadiazole-5-yl)-pyridine in 55% (0.550 g)yield. MS: m/z: 196.7 (M+1).

Step-2: The 2-(3-chloromethyl-[1,2,4]-oxadiazole-5-yl)-pyridine (0.550g, 2.8 mmol) was dissolved in acetone (20 ml). To the clear solution,sodium iodide (0.843 g, 5.62 mmol) and tetra-n-butyl-ammonium iodide(0.259 g, 0.70 mmol) were added. The reaction mixture was refluxed for 2hr. It was quenched by addition of water (20 ml) and extracted withethyl acetate (2×25 ml). The combined organic layer was dried overNa₂SO₄ and evaporated under vacuum to yield2-(3-Iodomethyl-[1,2,4]oxadiazole-5-yl)-pyridine in 90% (0.750 g) yield.MS: m/z: 288.1 (M+1).

Step-3: To the stirring solution of Example-7 (1.0 gm, 1.3 mmol) intoluene (10 ml) was added potassium hydride (0.16 g, 1.43 mmol) and18-crown-6-ether (0.048 g, 0.13 mmol) at a temperature 25-30° C. andstirred for 10 min. To this reaction mixture, step-2 product,2-(3-iodomethyl-[1,2,4]oxadiazole-5-yl)-pyridine (0.401 g, 1.43 mmol)was added and stirred for 1 hour at temperature 25-30° C. The reactionmixture was then poured in aqueous saturated ammonium chloride solution(20 ml) and the mixture was extracted with ethyl acetate (3×25 ml).Combined organic layer was dried over Na₂SO₄ and purified by usingsilica gel column chromatography (15% Acetone:Hexane). To afford step-3product as yellow solid in 65% (0.780 g) yield. MS: m/z: 946.3 (M+1).

Step-4: To the stirred solution of N-chlorosuccinimide (0.826 g, 6.18mmol) in toluene (15 ml) at 0° C. was added dimethyl sulfide (757 μl,10.3 mmol) to provide a complex. The complex was stirred at 0° C. foradditional for 30 minutes. The complex was cooled to and the solution ofstep-3 product (0.780 g, 0.825 mmol) dissolved in toluene ordichloromethane (10 ml) was added. The resulting reaction mixture wasstirred at −40° C. temperature for 2 hr and then allowed to warm at25-30° C. while stirring. Triethyl amine (1.14 ml, 8.25 mmol) was addedto the reaction mixture at 25-30° C. and it was stirred for additional30 minutes. The reaction mixture was poured in aqueous saturated sodiumbicarbonate solution and the mixture was extracted with dichloromethane(3×25 ml). The combined separated organic layer was dried over Na₂SO₄and was evaporated to provide residue. The residue was purified by usingsilica gel column chromatography (10% acetone:hexanes) to provide step-4product as a off white solid in 75% (0.582 g) yield. MS: m/z: 944.3(M+1).

Step-5: A mixture of step-4 compound (0.582 g, 0.617 mmol) and 70%HF-Pyridine solution (19.3 μl, 0.678 mmol) in acetonitrile (10 ml), wasstirred at 25-30° C. temperature for 2 hr. The solvent was evaporatedunder vacuum to obtain a crude residue. To the crude residue, water (20ml) was added and the mixture was extracted with dichloromethane (25ml×3). Combined separated organic layer was dried over Na₂SO₄ andevaporated under vacuum to obtain crude solid. The crude solid waspurified by using silica gel column chromatography (CHCl₃:MeOH; 90:10)to obtain title compound as white solid compound in 40% (0.230 g) yield.MS: m/z: 829.1 (M+1). Mp: 160-163° C.

Following examples were prepared by using above procedure and by usingreagent A.

Mp Mass Example T Reagent (A) (° C.) (M + 1) 260 CH₂-(5-(pyridin-4-yl)4-(3-chloromethyl-[1,2,4]- 151-155 829.1 [1,2,4]oxadiazol-3-yl)oxadiazol- 5-yl)-pyridine 261 CH₂-(5-(2-chloro2-chloro-3-(3-chloromethyl- 148-151 863.1 pyridin-3-yl)[1,2,4][1,2,4]-oxadiazol-5-yl)-pyriidne oxadiazol-3-yl) 262 CH₂-(5-(3-fluoro3-chloromethyl-5-(3-fluoro- 150-153 845.1 phenyl)[1,2,4] phenyl)-oxadiazol-3-yl) [1,2,4]-oxadiazole 263 CH₂-(5-(3-cyano3-(3-chloromethyl-[1,2,4]- 184-188 852.1 phenyl)[1,2,4]oxadiazol-oxadiazol- 3-yl) 5-yl)-benzonitrile 264 CH₂-(5-(3-chloro3-chloromethyl-5-(3- 133-136 861.1 phenyl)[1,2,4]oxadi- chlorophenyl)-azol-3-yl) [1,2,4]-oxadiazole 265 CH₂-(5-(pyridin-2-yl)3-(3-chloromethyl-[1,2,4]- 164-166 829.1 [1,2,4]oxadiazol-3-yl)oxadiazol- 5-yl)-pyridine 266 CH₂-(5-(2-methoxy2-methoxy-3-(3-chloromethyl- 123-125 859.1 pyridin-3-yl)[1,2,4][1,2,4]-oxadiazol-5-yl)-pyridine oxadiazol-3-yl) 267 CH₂-(5-(3-fluoro-4-3-chloromethyl-5-(3-fluoro-4- 161-165 875.1 methoxyphenyl)[1,2,4]methoxy-phenyl)- oxadiazol-3-yl) [1,2,4]-oxadiazole 268 CH₂-5-(2-fluoro2-fluoro-3-(3-chloromethyl- 132-135 847.1 pyridin-3-yl)[1,2,4][1,2,4]-oxadiazol-5-yl)-pyridine oxadiazol-3-yl) 269CH₂-(5-phenyl[1,2,4] 3-chloromethyl-5-phenyl-[1,2,4]- 189-192 827.1oxadiazol-3-yl) oxadiaozle 270 CH₂-(5-methyl[1,2,4]3-chloromethyl-5-methyl-[1,2,4]- 170-173 766.1 oxadiazol-3-yl)oxadiazole 271 CH₂-(5-(pyridazin-2- 2-(3-chloromethyl-[1,2,4]- 145-147831.1 yl)-[1,2,4]oxadiazol-3- oxadiazol- yl) 5-yl)-pyridazine 272CH₂-(5-trifluoromethyl 3-chloromethyl-5- 154-157 820.1[1,2,4]oxadiazol-3-yl) trifluoromethyl-[1,2,4]- oxadiazole 273 CH₂(5-(6-2-(3-chloromethyl-[1,2,4]- 194-197 843.1 methylpyridin-2-oxadiazol-5-yl)-6-methyl- yl)[1,2,4]oxadiazol-3- pyridine yl) 274CH₂-(5-(2-methyl- 3-chloromethyl-5-(2-methyl- 136-140 833.1oxazol-4-yl)-[1,2,4] oxazol-4-yl)-[1,2,4]-oxadiazole oxadiazol-3-yl) 275CH₂-(5-cyclopropyl 3-Chloromethyl-5-cyclopropyl- 175-178 791.1[1,2,4]oxadiazol-3-yl) [1,2,4]-oxadiazole 276 CH₂-(5-(5-methyl-2-(5-chloro methyl-[1,2,4]- — 844.1 pyridin-2-yl)-[1,2,4]oxadiazol-5-yl)-5-methyl- oxadiazol-3-yl) pyridine 277CH₂-(5-(5-cyclopropyl- 2-(5-chloromethyl-[1,2,4]- — 870.1pyridin-2-yl)-[1,2,4] oxadiazol-5-yl)-5-cyclopropyl- oxadiazol-3-yl)pyridine 278 CH₂-(5-(5-cyano- 2-(5-chloromethyl-[1,2,4]- — 855.1pyridin-2-yl)-[1,2,4] oxadiazol-5-yl)-5-cyano-pyridine oxadiazol-3-yl)279 CH₂-(5-(5-dimethyl 2-(5-chloromethyl-[1,2,4]- — 874.1amino-pyridin-2-yl)- oxadiazol-5-yl)-5-dimethylamino-[1,2,4]oxadiazol-3-yl) pyridine 280 CH₂-(5-(5-methoxy-2-(5-chloromethyl-[1,2,4]- — 860.1 pyridin-2-yl)-[1,2,4]oxadiazol-5-yl)-5-methoxy- oxadiazol-3-yl) pyridine 281 CH₂(5-(5-fluoro-2-(5-chloromethyl-[1,2,4]- — 848.1 pyridin-2-yl)-[1,2,4]oxadiazol-5-yl)-5-fluoro-pyridine oxadiazol-3-yl) 282 CH₂-(5-(5-chloro-2-(5-chloromethyl-[1,2,4]- — 864.1 pyridin-2-yl)-[1,2,4]oxadiazol-5-yl)-5-chloro-pyridine oxadiazol-3-yl) 283CH₂-(5-(pyrimidin-5- 5-(5-chloromethyl-[1,2,4]- — 831.1yl)-[1,2,4]oxadiazol-3- oxadiazol-5-yl)-pyrimidine yl)

Example-284 Compound of Formula I-f where T isCH₂-(3-(pyridin-2-yl)-isoxazol-5-yl)

Step-1: To the stirred solution of 2-pyridinecarboxaldehyde (2.00 ml,18.69 mmol) in methanol (20 ml) was added sodium acetate (1.83 g, 22.44mmol). To this reaction mixture hydroxylamine hydrochloride (1.51, 20.56mmol) was added and stirred for 2 hour at 20-30° C. temperature. Thereaction mixture was evaporated under vacuum to provide a crude mass. Tothe crude mass was stirred with water (20 ml), to effect precipitationand the separated solid was filtered under suction, dried under vacuumto provide step-1 product in 85% (1.93 g) yield. MS: m/z 123 (M+1).

Step 2: To the stirred solution of step-1 productpyridine-2-carbaldehyde oxime (1.80 g, 14.75 mmol) in DMF (20 ml), wasadded N-chloro succinimide (2.55 g, 19.19 mmol) and the reaction mixturewas stirred for 8 hour at 25-30° C. temperature. Ice-water was added (20ml) to the reaction mixture to effect precipitation and solid wasfiltered at suction and dried under vacuum to provide imidoyl chlorideas step-2 product imidoyl chloride in 70% (1.61 g) yield. This was useddirectly for the next reaction. MS: m/z 157 (M+1).

Step-3: To the stirred solution of product obtained from step A ofExample 185 (1.5 gm, 1.82 mmol) in toluene (15 ml) was added triethylamine (0.50 ml, 3.64 mmol). N-hydroxypyridine-2-carboximidoyl chloride(0.42 g, 2.73 mmol) was added to the reaction mixture and heated at 90°C. temperature for 12 hr. The reaction mixture was poured in aqueoussaturated ammonium chloride solution (20 ml). The mixture was extractedwith ethyl acetate (3×25 ml). Combined organic layer was dried overNa₂SO₄ and purified by using silica gel column chromatography (10%Acetone:Hexane) to provide off white solid as a step-3 product in 78%(1.34 g) yield. MS: m/z: 945 (M+1).

Step-4: To the stirred solution of N-chlorosuccinimide (1.27 g, 9.53mmol) in dichloromethane (15 ml) at 0° C. was added dimethyl sulfide(1.16 ml, 15.88 mmol). The reaction mixture was stirred at 0° C. for 30min. The step-3 product (1.2 gm, 1.27 mmol) dissolved in dichloromethane(10 ml) was added to the reaction mixture at −40° C. The resultingreaction mixture was stirred at the same temperature for 2 hr andallowed to warm at 25-30° C. temperature. Triethyl amine (1.76 ml, 12.71mmol) was added and it was stirred for additional 30 min. The reactionmixture was poured in aqueous saturated sodium bicarbonate solution (100ml) and the mixture was extracted with dichloromethane (3×25 ml). Thecombined organic layer was dried over Na₂SO₄ and purified by usingsilica gel column chromatography (10% Acetone:Hexane) to provide step-4product as a off white solid in 75% (0.9 g) yield. MS: m/z: 943 (M+1).

Step-5: The mixture of step-4 product (0.9 g, 0.90 mmol) and 70%HF-Pyridine solution (41 μl, 1.43 mmol) dissolved in acetonitrile (10ml) was stirred at 25-30° C. for 2 hr under N₂ atmosphere. Aftercompletion of reaction, solvent was evaporated under vacuum to obtaincrude product. Water (20 ml) was added to the crude product andextracted with dichloromethane (3×25 ml). Combined organic layer wasdried over sodium sulphate and evaporated under vacuum to obtain crudemass. The crude mass was purified by using silica gel columnchromatography (10% MeOH:CHCl₃) to obtain title compound in 50% (0.39 g)yield. Mp: 198-201° C., MS: m/z: 829 (M+1).

Following examples were prepared by using above procedure and by usingreagent A.

Ex- am- Mp Mass ple T Reagent (A) (° C.) (M + 1) 285CH₂(3-(pyridin-3-yl)- N-hydroyxpyridine-3- 172-174 828.1 isoxazol-5-yl)carboximidoyl chloride 286 CH₂-(3-(3-fluoro 3-fluoro-N-hydroxy 146-148845.1 phenyl)-isoxazol-5-yl) benzene-carboximi- doyl chloride 287CH₂-(3-(3-chloro 3-chloro-N-hydroxy 176-180 861.1 phenyl)-isoxazol-5-yl)benzene- carboximidoyl choride 288 CH₂(3-(4-fluoro- 4-fluoro-N-hydroxy212-214 845.1 phenyl)- benzene- isoxazol-5-yl) carboximidoyl chloride289 CH₂-(3-(3-methoxy N-hydroxy-3- 217-221 857.1 phenyl)-isoxazol-5-yl)methoxy-benzene- carboximidoyl chloride 290 CH₂-(3-phenyl-N-hydroxybenzene- 223-225 827.1 isoxazol-5-yl) carboximidoyl chloride291 CH₂-(3-methyl- (1Z)-N-hydroxy 185-189 765.1 isoxazol-5-yl)ethanimidoyl chloride 292 CH₂-(3-(6-methoxy- N-hydroxy-6- 180-182 858.1pyridin-2-yl)-isoxazol- methoxypyridine-2- 5-yl) carboximidoyl chloride293 CH₂(3-(2-methoxy- N-hydroxy-6- 184-186 858.1 pyridin-5-yl)-isoxazol-methoxypyridine-3- 5-yl) carboximidoyl chloride 294 CH₂-(3-(5-methyl-N-hydroxy-5-methyl — 843.1 pyridin-2-yl)-isoxazol- pyridine-2-carbox-5-yl) imidoyl chloride 295 CH₂-(3-(5-cyclo- 5-cyclopropyl-N- — 869.1propyl- hydroxy-pyridine-2- pyridin-2-yl)-isoxazol- carboximidoylchloride 5-yl) 296 CH₂-(3-(5-cyano- 5-cyano-N-hydroxy- — 854.1pyridin-2-yl)-isoxazol- pyridine-2-carbox- 5-yl) imidoyl chloride 297CH₂-(3-(5-dimethyl 5-(dimethylamino)-N- — 873.1 amino-pyridin-2-yl)-hydroxy-pyridine-2- isoxazol-5-yl) carboximidoyl chloride 298CH₂-(3-(5-methoxy- N-hydroxy-5- — 859.1 pyridin-2-yl)-isoxazol-methoxypyridine-2- 5-yl) carboximidoyl chloride 299 CH₂-(3-(5-fluoro-5-fluoro-N-hydroxy- — 847.1 pyridin-2-yl)-isoxazol- pyridine-2- 5-yl)carboximidoyl chloride 300 CH₂-(3-(5-chloro- 5-chloro-N-hydroxy- — 863.1pyridin-2-yl)-isoxazol- pyridine-2- 5-yl) carboximidoyl chloride 301CH₂-(3-(pyrimidin- N-hydroxy- — 830.1 5-yl)-isoxazol-5-yl) pyrimidine-5-carboximidoyl chloride

Example-302 Compound of Formula I-f where T isCH₂-(5-(pyridin-3-yl)-isoxazol-3-yl)

Step A: To the stirred solution of Example 7 (1.0 g, 1.3 mmol) intoluene (15 ml) is added potassium tert-butoxide (0.16 g, 1.43 mmol) and18-crown-6-ether (0.048 g, 0.13 mmol) at 25-30° C. temperature. Thereaction mixture is stirred for 10 min at 25-30° C. temperature.2-(3-Chloromethyl-isoxazol-5-yl)-pyridine (0.28 mol, 1.43 mmol) is addedto the reaction mixture and it is stirred for additional 1 hour. It isquenched by pouring it in aqueous saturated ammonium chloride solution(20 ml). The mixture is extracted with ethyl acetate (3×25 ml). Combinedorganic layer is dried over Na₂SO₄ and purified by using silica gelcolumn chromatography (10% Acetone:Hexane) to provide step-1 product asa pale yellow solid in 48% (0.57 g) yield. MS: m/z: 945.1 (M+1).

Step B: To the stirred solution of N-chlorosuccinimide (0.6 g, 4.5 mmol)in dichloromethane (15 ml) at 0° C. is added dimethyl sulfide (0.48 ml,7.5 mmol). The reaction mixture is stirred at 0° C. for 30 min. Thestep-1 product (0.55 gm, 0.6 mmol) dissolved in dichloromethane (10 ml)is added to the reaction mixture at −40° C. The resulting reactionmixture is stirred at the same temperature for 2 hr and allowed to warmat 25-30° C. temperature. Triethyl amine (0.84 ml, 6.0 mmol) is addedand it is stirred for additional 30 min. The reaction mixture is pouredin aqueous saturated sodium bicarbonate solution (100 ml) and themixture is extracted with dichloromethane (3×25 ml). The combinedorganic layer is dried over Na₂SO₄ and purified by using silica gelcolumn chromatography (10% Acetone:Hexane) to provide step-4 product asa off white solid in 72% (0.4 g) yield. MS: m/z: 943 (M+1).

Step C: The mixture of step-4 product (0.4 g, 0.42 mmol) and 70%HF-Pyridine solution (18 μl, 0.64 mmol) dissolved in acetonitrile (10ml) is stirred at 25-30° C. for 2 hr under N₂ atmosphere. Aftercompletion of reaction, solvent is evaporated under vacuum to obtaincrude product. Water (20 ml) is added to the crude product and extractedwith dichloromethane (3×25 ml). Combined organic layer is dried oversodium sulphate and evaporated under vacuum to obtain crude mass. Thecrude mass is purified by using silica gel column chromatography (10%MeOH:CHCl₃) to obtain title compound in 65% (0.25 g) yield. MS: m/z: 829(M+1).

Following examples are prepared by using above procedure and by usingreagent A.

Ex- am- Mass ple T Reagent A (M + 1) 303 CH₂-(5-(3-fluorophenyl)-3-chloromethyl-5-(3-fluoro- 845.1 isoxazol-3-yl) phenyl)-isoxazole 304CH₂-(5-(3-chlorophenyl)- 3-chloromethyl-5-(3-chloro- 861.1isoxazol-3-yl) phenyl)-isoxazole 305 CH₂-(5-(4-fluorophenyl)-3-chloromethyl-5-(4-fluoro- 845.1 isoxazol-3-yl) phenyl)-isoxazole 306CH₂-(5-(3-methoxy 3-chloromethyl-5-(3- 857.1 phenyl)-isoxazol-3-yl)methoxy- phenyl)-isoxazole 307 CH₂-(5-phenyl)-isoxazol-3-chloromethyl-5-phenyl- 827.1 3-yl) isoxazole 308CH₂-(5-methyl)-isoxazol- 3-chloromethyl-5-methyl- 765.1 3-yl) isoxazole309 CH₂-(5-(6-methoxy-pyri- 2-(3-chloromethyl- 858.1din-2-yl)-isoxazol-3-yl) isoxazol-5- yl)-6-methoxy-pyridine 310CH₂-(5-(2-methoxy-pyri- 5-(3-chloromethyl-isoxazol- 858.1din-5-yl)-isoxazol-3-yl) 5-yl)-2-methoxy- pyridine 311CH₂-(5-(5-methyl-pyri- 2-(3-chloromethyl-isoxazol- 843.1din-2-yl)-isoxazol-3-yl) 5-yl)-5-methyl-pyridine 312CH₂-(5-(5-cyclopropyl- 2-(3-chloromethyl-isoxazol- 869.1pyridin-2-yl)-isoxazol-3- 5-yl)-5-cyclopropyl- yl) pyridine 313CH₂-(5-(5-cyano-pyridin- 2-(3-chloromethyl-isoxazol- 854.12-yl)-isoxazol-3-yl) 5-yl)-5-cyano-pyridine 314 CH₂-(5-(5-dimethylami-2-(3-chloromethyl-isoxazol- 873.1 no-pyridin-2-yl)-5-yl)-5-dimethylamino- isoxazol-3-yl) pyridine 315CH₂-(5-(5-methoxy-pyri- 2-(3-chloromethyl-isoxazol- 859.1din-2-yl)-isoxazol-3-yl) 5-yl)-5-methoxy-pyridine 316CH₂-(5-(5-fluoro-pyridin- 2-(3-chloromethyl-isoxa- 847.12-yl)-isoxazol-3-yl) diazol-5-yl)-5- fluoro-pyridine 317CH₂-(5-(5-chloro-pyri- 2-(3-chloromethyl-isoxazol- 863.1din-2-yl)-isoxazol-3-yl) 5-yl)-5-chloro-pyridine 318CH₂-(pyrimidin-5-yl)- 5-(3-chloromethyl-isoxazol- 830.1 isoxazol-3-yl)5-yl)-pyrimidine 319 CH₂CH₂-(4-(pyridin-2- 2-[1-(2-Chloro-ethyl)-1H-842.1 yl)-1H-imidazol-1-yl) imidazol-4-yl]-pyridine 320CH₂CH₂-(4-(pyridin-3- 3-[1-(2-Chloro-ethyl)-1H- 842.1yl)-1H-imidazol-1-yl) imidazol-4-yl]-pyridine 321 CH₂CH₂-(4-(6-methyl-2-[1-(2-Chloro-ethyl)-1H- 856.1 pyridin-2-yl)-1H-imidazol-4-yl]-6-methyl- imidazol-1-yl) pyridine 322CH₂CH₂-(4-(4-methoxy- 2-[1-(2-Chloro-ethyl)-1H- 872.1 pyridin-2-yl)-1H-imidazol-4-yl]-4-methoxy- imidazol-1-yl) pyridine 323CH₂-(4-(pyridin-2-yl)- 2-(4-Chloromethyl- 828.1 pyrazol-4-yl) pyrazol-1-yl)-pyridine 324 CH₂-(4-(pyridin-3-yl)- 3-(4-Chloromethyl-pyrazol- 828.1pyrazol-4-yl) 1-yl)-pyridine 325 CH₂-(4-(6-methyl-pyri-2-(4-Chloromethyl-pyrazol- 842.1 din-2-yl)-pyrazol-4-yl) 1-yl)-6-methyl-pyridine 326 CH₂-(4-(4-methoxy-pyri- 2-(4-Chloromethyl-pyrazol- 858.1din-2-yl)-pyrazol-4-yl) 1-yl)-4-methoxy-pyridine 327CH₂-(4-(5-methoxy-pyri- 2-(4-Chloromethyl-pyrazol- 858.1din-2-yl)-pyrazol-4-yl) 1-yl)-5-methoxy-pyridine 328CH₂-(1-(pyridin-2-yl)- 2-(4-Chloromethyl- 828.1 1H-imidazol-4-yl)imidazol-1-yl)-pyridine 329 CH₂-(1-(pyridin-3-yl)- 3-(4-Chloromethyl-828.1 1H-imidazol-4-yl) imidazol- 1-yl)-pyridine 330 CH₂-(1-(6-methyl-2-(4-Chloromethyl- 842.1 pyridin-2-yl)-1H- imidazol-1- imidazol-4-yl)yl)-6-methyl-pyridine 331 CH₂-(1-(4-methoxy- 2-(4-Chloromethyl- 858.1pyridin-2-yl)-1H- imidazol-1- imidazol-4-yl) yl)-4-methoxy-pyridine 332CH₂-(1-(5-methoxy- 2-(4-Chloromethyl- 858.1 pyridin-2-yl)-1H-imidazol-1- imidazol-4-yl) yl)-5methoxy-pyridine 333CH₂-(2-(pyridin-2-yl)- 2-(4-Chloromethyl- 829.1 oxazol-4-yl) oxazol-2-yl)-pyridine 334 CH₂-(2-(pyridin-3-yl)- 3-(4-Chloromethyl- 829.1oxazol-4-yl) oxazol-2- yl)-pyridine 335 CH₂-(2-(6-methyl-pyri-2-(4-Chloromethyl- 843.1 din-2-yl)-oxazol-4-yl) oxazol-2-yl)-6-methyl-pyridine 336 CH₂-(2-(4-methoxy-pyri- 2-(4-Chloromethyl-859.1 din-2-yl)-oxazol-4-yl) oxazol-2- yl)-4-methoxy-pyridine 337CH₂-(2-(5-methoxy-pyri- 2-(4-Chloromethyl- 859.1 din-2-yl)-oxazol-4-yl)oxazol-2- yl)-5-methoxy-pyridine

Example-338 Compound of Formula I-f where Q is CN

A mixture of Example 8 (0.95 g, 1.3 mmol) and 70% hydrogen fluoride inpyridine (50 μl, 1.8 mmol) in acetonitrile (15 ml) was stirred underinert atmosphere at a temperature between 25-30° C. for 3 h. The solventwas evaporated under vacuum and the residue obtained was dissolved inethyl acetate (25 ml) and washed with water (2×10 ml). The combinedorganic layer was dried over Na₂SO₄ and evaporated under reducedpressure to provide crude solid which on trituration in diethyl etherafforded pale yellow solid as the title compound in 60% (0.58 g) yield.MP: 230-232° C., Mass: m/z: 638.1 (M+1).

Example-339 Compound of Formula I-f where T is H

A mixture of Example 9 (0.95 g, 1.2 mmol) and 70% hydrogen fluoride inpyridine (50 μl, 1.8 mmol) in acetonitrile (15 ml) was stirred underinert atmosphere at a temperature between 25-30° C. for 15 h. Thesolvent was evaporated under vacuum and the residue obtained wasdissolved in ethyl acetate (25 ml) and washed with water (2×10 ml). Thecombined organic layer was dried over Na₂SO₄ and evaporated underreduced pressure to provide crude solid which on trituration in diethylether afforded pale yellow solid as the title compound in 75% (0.7 g)yield. MP: 174-176° C., Mass: m/z: 671.1 (M+1).

Example-340 Compound of Formula I-f where T is (CH₂)₂CH₃

To a stirring solution of Example 179 (0.3 gm, 0.37 mm) in THF (10 ml)was added 10% Pd/C (30 mg, 10%) and stirred under H₂ atmosphere for 15hr. The reaction mixture was filtered through celite and concentratedunder reduced pressure. Crude solid was triturated in diethyl etheraffording white solid. Yield: 250 mg (84%), MP: 182-184° C., Mass: m/z:713.1 (M+H).

Following examples were prepared as per the procedure mentioned above byusing the corresponding unsaturated starting material.

Starting Mp Example material T (° C.) Mass (M + 1) 341 Example 205CH₂CH₂CH(CH₃)₂ 244-246 741.1 342 Example 208 CH₂(CH₂)₂Ph 172-174 789.1

While the present invention has been described in terms of its specificembodiments, certain modifications and equivalents will be apparent tothose skilled in the art and are intended to be included within thescope of the present invention.

1. Compounds having the structure of Formula I:

and their pharmaceutically acceptable salts, pharmaceutically acceptableenantiomers or diastereomers, wherein * indicates a chiral center; R₁ ishydrogen or methyl; R₂ is hydrogen or hydroxyl protecting group, whereinhydroxyl protecting groups are selected from the group consisting oftriethylsilyl, trimethylsilyl, acetyl, benzoyl, methoxymethyl, benzyl,methoxyethoxymethyl or tertbutyldimethylsilyl; Q is Het or

wherein Het is selected from

wherein R₃ is one or more substituent selected from the group consistingof NO₂, CN, halogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, CH₂CONH₂, CH₂CO₂Et,CH₂CN, CH₂CH₂OH, CH₂OCH₂CH₂OCH₃, NH₂, substituted C₁-C₆ alkyl andsubstituted C₂-C₆ alkenyl; T is selected from the group consisting of:hydrogen, —(CH₂)_(m)—R₅, —(CH₂)_(m)—CH═CH—R₅, —(CH₂)_(m)—C═C—R₅,(CH₂)_(m)—R₅, -A-(CH₂)_(m)—CH═CH—R₅, -A-(CH₂)_(m)—C═C—R₅,—(CH₂)_(m)—B—R₅, (CH₂)_(m)—B—R₅, —(CH₂)_(m)—X—R₆, —(CH₂)_(m)—B-X—R₆,—(CH₂)_(m)—CH═CH—X—R₆, —(CH₂)_(m)—C≡C—X—R₆, -A-(CH₂)_(m)—X—R₆,-A-(CH₂)_(m)—B—X—R₆, -A-(CH₂)_(m)—CH═CH—X—R₆ and -A-(CH₂)_(m)—C≡C—X—R₆;wherein, m is 0, 1, 2 or 3; R₅ is selected from the group consisting of:hydrogen, cyano, halogen, hydroxyl, CO₂(C₁-C₆ alkyl), CO NR_(a)R_(b),NR_(a)R_(b), C₁-C₆ alkyl or substituted C₁-C₆ alkyl, C₂-C₆ alkenyl orsubstituted C₂-C₆ alkenyl, C₂-C₆ alkynyl or substituted C₂-C₆ alkynyl, 6membered substituted or unsubstituted aryl, 5-6 membered substituted orunsubstituted heteroaryl, 3-6 membered substituted or unsubstitutedcycloalkyl and 3-6 membered substituted or unsubstituted heterocyclyl; wherein R_(a) and R_(b) are independently hydrogen, C₁-C₆ alkyl or R_(a) and R_(b) together with the nitrogen to which they are attachedform a 5-6 membered heterocyclic ring wherein the heterocycle has one ormore heteroatoms selected from N, O, S; A is —CO— or —CONH—; B is —O—,—S—, —SO—, —SO₂—, —CO—, —CONH—, —CON(CH₃)—, —NHCONH—, —C(NH₂)═N—O—,

wherein R₈ is a substitutent at any one of carbon of the heterocycle, R₈is selected from the group comprising of hydrogen, C₁-C₆ alkyl,substituted C₁-C₆ alkyl, C₂-C₆ alkenyl and substituted C₂-C₆ alkenyl; Xis a 6 membered aryl or a 5-6 membered heteroaryl; R₆ is aryl,heteroaryl, substituted aryl or substituted heteroaryl; Y′ is hydrogenand Y is OR₇, wherein R₇ is hydrogen or

wherein R_(2′) is hydrogen, (when R_(2′) is hydrogen, R₇ is designatedas cladinose) or hydroxyl protecting group, wherein hydroxyl protectinggroups are selected from the group consisting of triethylsilyl,trimethylsilyl, acetyl, benzoyl, methoxymethyl, methoxyethoxymethyl,benzyl or tertbutyldimethylsilyl; or Y and Y′ together with the carbonto which they are attached form C═O.
 2. The compound of claim 1, whereinR₁ is CH₃ and Het is

wherein R₃ is one or more substituent selected from C₁-C₆ alkyl, C₂-C₆alkenyl, CH₂CONH₂, CH₂CO₂(C₁-C₆ alkyl), CH₂CN, CH₂CH₂OH, CH₂OCH₂CH₂OCH₃.3. The compound of claim 1, wherein Q is


4. The compound of claim 3, wherein T is selected from —(CH₂)_(m)—R₅,—(CH₂)_(m)—C≡C—R₅, —(CH₂)_(m)—C═C—R₅, -A-(CH₂)_(m)—R₅,-A-(CH₂)_(m)—CH═CH—R₅, -A-(CH₂)_(m)—C═C—R₅, —(CH₂)_(m)—B—R₅,-A-(CH₂)_(m)—B—R₅, wherein m is 1 or 2; A is —CO—; B is piperazinyl; R₅is substituted/unsubstituted phenyl or heteroaryl; wherein heteroaryl isselected from pyridin-4-yl, pyridin-3-yl, pyridin-2-yl, pyrimidinyl,pyrazzolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, oxazolyl orisoxazolyl; phenyl or heteroaryl may be substituted with one or moresubstituents selected from the group comprising of C₁-C₆ alkyl, C₁-C₆alkoxy, cyano, halogen, dimethylamino.
 5. The compound of claim 1,wherein T is selected from —(CH₂)_(m)—X—R₆, —(CH₂)_(m)—CH═CH—X—R₆,—(CH₂)_(m)—C═C—X—R₆, -A-(CH₂)_(m)—X—R₆, -A-(CH₂)_(m)—CH═CH—X—R₆,-A-(CH₂)_(m)—C≡C—X—R₆.
 6. The compound of claim 5, wherein X—R₆ is

wherein R₆ is phenyl, substituted phenyl, heteroaryl or substitutedheteroaryl; wherein heteroaryl is selected from one or more ofpyridin-4-yl, pyridin-3-yl, pyridin-2-yl, pyrimidinyl, pyrazzolyl,imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, oxazolyl or isoxazolyl;wherein the phenyl or heteroaryl is substituted with one or moresubstituents selected from the group comprising of C₁-C₆ alkyl, C₁-C₆alkoxy, cyano, halogen and dimethylamino.
 7. The compound of claim 1,wherein T is —(CH₂)_(m)—X—R₆, wherein R₆.
 8. The compound of claim 7,wherein X—R₆ is

wherein R₆ is phenyl, substituted phenyl, heteroaryl or substitutedheteroaryl.
 9. The compound of claim 8, wherein heteroaryl ispyridin-4-yl, pyridin-3-yl, pyridin-2-yl, pyrimidinyl, pyrazzolyl,imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, oxazolyl or isoxazolyl.10. The compound of claim 8, wherein the phenyl or heteroaryl issubstituted with one or more substituents selected from the groupcomprising of C₁-C₆ alkyl, C₁-C₆ alkoxy, cyano, halogen, dimethylamino.11. A compound of Formula I-c, wherein the compound is selected from thegroup consisting of:

Compound of Formula I-c, where T isCH₂CH₂-(1-(3-methoxy)phenyl-1H-[1,2,3]triazol-4-yl), R₁ is CH₃; Compoundof Formula I-c, where T is COCH═CH-(pyridin-4-yl), R₁ is CH₃; Compoundof Formula I-c, where T is COCH═CH-(pyridin-3-yl), R₁ is CH₃; Compoundof Formula I-c, where T is CO(CH₂)₂-(pyridin-3-yl), R₁ is CH₃; Compoundof Formula I-c, where T is CO(CH₂)₂-(3-methoxy)phenyl, R₁ is CH₃;Compound of Formula I-c, where T is CO(CH₂)₂-(4-methoxy)phenyl, R₁ isCH₃; Compound of Formula I-c, where T isCO(CH₂)₂-(4-dimethylamino)phenyl, R₁ is CH₃; Compound of Formula I-c,where T is CO(CH₂)₂-(3-cyano)phenyl, R₁ is CH₃; Compound of Formula I-c,where T is COCH₂O-(3-chloro)phenyl, R₁ is CH₃; Compound of Formula I-c,where T is CO(CH₂)₂-(3,5-dimethoxy)phenyl, R₁ is CH₃; Compound ofFormula I-c, where T is CO(CH₂)₂-(2,3-dimethoxy)phenyl, R₁ is CH₃;Compound of Formula I-c, where T is CO(CH₂)₂-(3-fluoro)phenyl, R₁ isCH₃; Compound of Formula I-c, where T isCO(CH₂)₂-(4-(2-methylphenyl)-piperazinyl), R₁ is CH₃; Compound ofFormula I-c, where T is CO(CH₂)₂-(4-(phenyl)piperazinyl), R₁ is CH₃;Compound of Formula I-c, where T isCO(CH₂)₂-(1-(4-methoxyphenyl)-1H-[1,2,3]triazol-4-yl), R₁ is CH₃;Compound of Formula I-c, where T isCO(CH₂)₂-(1-(pyridin-3-yl)-[1,2,3]triazol-4-yl), R₁ is CH₃; Compound ofFormula I-c, where T isCO(CH₂)₂-(1-(4-fluorophenyl)-1H-[1,2,3]triazol-4-yl), R₁ is CH₃;Compound of Formula I-c, where T isCO(CH₂)₂-(1-(3-methylphenyl)-1H-[1,2,3]triazol-4-yl), R₁ is CH₃;Compound of Formula I-c, where T isCO(CH₂)₂-(1-(3-chlorophenyl)-1H-[1,2,3]triazol-4-yl), R₁ is CH₃;Compound of Formula I-c, where T isCO(CH₂)₂-(3-(3-bromophenyl)-[1,2,4]oxadiazol-5-yl), R₁ is CH₃; Compoundof Formula I-c, where T isCO(CH₂)₂-(3-(3-fluorophenyl)-[1,2,4]oxadiazol-5-yl), R₁ is CH₃; Compoundof Formula I-c, where T isCO(CH₂)₂-(3-(pyridin-4-yl)-[1,2,4]oxadiazol-5-yl), R₁ is CH₃; Compoundof Formula I-c, where T isCO(CH₂)₂-(3-(pyridin-3-yl)-[1,2,4]oxadiazol-5-yl), R₁ is CH₃; Compoundof Formula I-c, where T isCO(CH₂)₂-[3-(4-methoxyphenyl)-[1,2,4]oxadiazol-5-yl], R₁ is CH₃;Compound of Formula I-c, where T isCO(CH₂)₂-(1-(2-methoxy)phenyl)-1H-[1,2,3]triazol-4-yl), R₁ is CH₃;Compound of Formula I-c, where T isCO(CH₂)₂-(1-(3-fluorophenyl)-1H-[1,2,3]triazol-4-yl), R₁ is CH₃;Compound of Formula I-c, where T isCO(CH₂)₂-(3-phenyl-[1,2,4]oxadiazol-5-yl), R₁ is CH₃; Compound ofFormula I-c, where T isCO(CH₂)₂-(3-naphthalen-2-yl-[1,2,4]oxadiazol-5-yl), R₁ is CH₃ andCompound of Formula I-c, where T isCO(CH₂)₂-(1-(3,5-difluoro-phenyl)-1H-[1,2,3]triazol-4-yl), R₁ is CH₃.12. A compound of Formula I-f, wherein the compound is selected from thegroup consisting of:

Compound of Formula I-f, where T is CH₂C(F)═CH₂; Compound of FormulaI-f, where T is CH₂CH≡C-(2-fluoropyridin-5-yl); Compound of Formula I-f,where T is CH₂CH≡C-(pyridin-3-yl); Compound of Formula I-f, where T isCH₂-(3-chlorophenyl); Compound of Formula I-f, where T isCH₂-(2-fluorophenyl); Compound of Formula I-f, where T isCH₂-(4-(1H-[1,2,4]-triazol)phenyl); Compound of Formula I-f, where T isCH₂-(5-phenyl[1,3,4]oxadiazol-2-yl); Compound of Formula I-f, where T isCH₂-(5-(pyridin-3-yl)[1,3,4]oxadiazol-2-yl); Compound of Formula I-f,where T is CH₂-(5-(3-fluorophenyl)[1,3,4]oxadiazol-2-yl); Compound ofFormula I-f, where T is CH₂-(5-(pyridin-2-yl)[1,3,4]oxadiazol-2-yl);Compound of Formula I-f, where T is CH₂-(3-phenyl[1,2,4]oxadiazol-5-yl);Compound of Formula I-f, where T isCH₂-(3-(3-fluorophenyl)[1,2,4]oxadiazol-5-yl); Compound of Formula I-f,where T is CH₂-(3-(3-chlorophenyl)[1,2,4]oxadiazol-5-yl); Compound ofFormula I-f, where T is CH₂-(3-(4-chlorophenyl)[1,2,4]oxadiazol-5-yl);Compound of Formula I-f, where T isCH₂-(3-(4-methoxyphenyl)[1,2,4]oxadiazol-5-yl); Compound of Formula I-f,where T is CH₂-(3-(pyridin-3-yl)[1,2,4]oxadiazol-5-yl); Compound ofFormula I-f, where T is CH₂-(3-(pyridin-2-yl)[1,2,4]oxadiazol-5-yl);Compound of Formula I-f, where T isCH₂-(3-cyclopropyl[1,2,4]oxadiazol-5-yl); Compound of Formula I-f, whereT is CH₂-(5-phenyl[1,2,4]oxadiazol-3-yl); Compound of Formula I-f, whereT is CH₂-(5-(pyridin-2-yl)[1,2,4]oxadiazol-3-yl); Compound of FormulaI-f, where T is CH₂-(5-(2-fluoropyridin-3-yl)[1,2,4]oxadiazol-3-yl);Compound of Formula I-f, where T isCH₂-(5-cyclopropyl[1,2,4]oxadiazol-3-yl); Compound of Formula I-f, whereT is CH₂-(5-methyl[1,2,4]oxadiazol-3-yl); Compound of Formula I-f, whereT is CH₂-(5-(pyridazin-2-yl)[1,2,4]oxadiazol-3-yl); Compound of FormulaI-f, where T is CH₂-(5-(2-methyl-thiazol-4-yl)[1,2,4]oxadiazol-3-yl);Compound of Formula I-f, where T isCH₂-(3-(3-fluorophenyl)-isoxazol-5-yl); Compound of Formula I-f, where Tis CH₂-(3-(3-chlorophenyl)-isoxazol-5-yl); Compound of Formula I-f,where T is CH₂-(3-(4-fluorophenyl)-isoxazol-5-yl); Compound of FormulaI-f, where T is CH₂-(3-(pyridin-2-yl)-isoxazol-5-yl); Compound ofFormula I-f, where T is CH₂-(3-phenyl-isoxazol-5-yl); Compound ofFormula I-f, where T is CH₂-(3-(5-methyl-pyridin-2-yl)-isoxazol-5-yl);Compound of Formula I-f, where T isCH₂-(3-(5-cyclopropyl-pyridin-2-yl)-isoxazol-5-yl); Compound of FormulaI-f, where T is CH₂-(3-(5-cyano-pyridin-2-yl)-isoxazol-5-yl); Compoundof Formula I-f, where T isCH₂-(3-(5-dimethylamino-pyridin-2-yl)-isoxazol-5-yl); Compound ofFormula I-f, where T is CH₂-(3-(5-methoxy-pyridin-2-yl)-isoxazol-5-yl);Compound of Formula I-f, where T isCH₂-(3-(5-fluoro-pyridin-2-yl)-isoxazol-5-yl); Compound of Formula I-f,where T is CH₂-(3-(5-chloro-pyridin-2-yl)-isoxazol-5-yl) and Compound ofFormula I-f where T is CH₂-(3-(pyrimidin-5-yl)-isoxazol-5-yl).
 13. Apharmaceutical composition comprising a therapeutically effective amountof a compound as defined in claim 1, optionally together with one ormore pharmaceutically acceptable carriers, excipients or diluents.
 14. Amethod for treating bacterial or portozoa infections in a human or ananimal, comprising administering to said animal or human, atherapeutically effective amount of a compound of claim
 1. 15. Themethod for treating bacterial or protozoa infections in an animal or ahuman comprising administering to said animal or human, a pharmaceuticalcomposition according to claims
 13. 16. A process for preparing acompound of Formula I as defined in claim 1 or its pharmaceuticallyacceptable salts, pharmaceutically acceptable enantiomers ordiastereomers, the process comprising one or more of the following stepsof: a) treating the compound of Formula VIIa or VIIb with a suitablecarboxylic acid reagent of the Formula R₉—COOH, wherein R₉ represents—(CH₂)_(m)—R₅, —(CH₂)_(m)—CH═CH—R₅, —(CH₂)_(m)—C═C—R₅, —(CH₂)_(m)—B—R₅,—(CH₂)_(m)—CH═CH—R₅, —(CH₂)_(m)—C═C—R₅, —(CH₂)_(m)—X—R₆,—(CH₂)_(m)—CH═CH—X—R₆, —(CH₂)_(m)—C≡C—X—R₆, in presence of esterifyingagent to give corresponding compound of Formula XIa or XIb, wherein * isa chiral centre, and subjecting the resulting compound to one or more ofthe following reactions:

i) deprotecting the hydroxyl protecting groups of compound of FormulaXIa to give the corresponding macrolide of Formula XIIa;

 or ii) oxidizing the compound of Formula XIb to give the 3-ketonederivative of Formula XIII;

iii) deprotecting the hydroxyl protecting groups to give thecorresponding ketolide of Formula XIIb; b) treating the compound ofFormula VIIa or VIIb with a suitable isocyanate reagent of FormulaR₉—N═C═O, wherein R₉ represents —(CH₂)_(m)—R₅, —(CH₂)_(m)—CH═CH—R₅,—(CH₂)_(m)—C═C—R₅, —(CH₂)_(m)—B—R₅, —(CH₂)_(m)—CH═CH—R₅,—(CH₂)_(m)—C≡C—R₅, —(CH₂)_(m)—X—R₆, —(CH₂)_(m)—CH═CH—X—R₆,—(CH₂)_(m)—C═C—X—R₆, wherein R₅, R₆, X, B and m are as defined above, togive compound of Formula XIVa or XIVb, wherein * is a chiral centre, andsubjecting the resulting compound to one or more of the followingreactions:

i) deprotecting the hydroxyl protecting groups of compound of FormulaXIVa to give the corresponding macrolide of Formula XVa;

 or ii) converting the 3-hydroxyl derivative XIVb to 3-ketone derivativeof Formula XVI;

iii) deprotecting the hydroxyl protecting groups of XVI to give thecorresponding ketolide of Formula XVb; c) treating the compound ofFormula VIIa or VIIb with a suitable alkylating reagent of Formulahalo-R₉, wherein R₉ represents —(CH₂)_(m)—R₅, —(CH₂)_(m)—CH═CH—R₅,—(CH₂)_(m)—C═C—R₅, —(CH₂)_(m)—B—R₅, —(CH₂)_(m)—CH═CH—R₅,—(CH₂)_(m)—C≡C—R₅, —(CH₂)_(m)—X—R₆, —(CH₂)_(m)—CH═CH—X—R₆,—(CH₂)_(m)—C═C—X—R₆, wherein B, X, R₅, R₆ and m are as defined above andhalo is a chlorine, bromine or iodine, in presence of base to givecompound of Formula XVIa or XVIb, wherein * is a chiral centre, andsubjecting the resulting compound XVIa or XVIb, to one or more of thefollowing reactions:

iv) deprotecting the hydroxyl protecting groups of Formula XVIa to givethe corresponding macrolide of Formula XVIIa;

 or v) converting the 3-hydroxyl derivative of Formula XVIa to 3-oxoderivative of Formula XVIIb′;

iii) deprotecting the hydroxyl protecting groups of compound of FormulaXVIIb′ to give the corresponding ketolide of Formula XVIIb; d) treatingthe compound of Formula XVIIIa or XVIIIb with a suitable halo-arylreagent of Formula halo-R₅ or halo-X—R₆ in the presence of suitablepalladium catalyst and phosphine derivative under heck coupling reactionconditions to give compound of Formula XIXa or XIXb,

wherein G is —(CH₂)_(m)—, -A-(CH₂)_(m)—; U is —R₅, —X—R₆ and * is achiral centre; and subjecting the resulting compound to one or more ofthe following reactions: i) deprotecting the hydroxyl protecting groupsto give the corresponding macrolide of Formula XXa;

 or ii) converting the 3-hydroxyl derivative XIXb to 3-ketone of FormulaXXb′;

iii) deprotecting the hydroxyl protecting groups of Formula XXb′ to givethe corresponding ketolide of Formula XXb; e) treating the compound ofFormula XXIa or XXIb with a suitable halo-aryl reagent in the presenceof suitable palladium catalyst under sonagashira coupling reactionconditions to give corresponding compound of Formula XXIIa or XXIIb,

wherein G is —(CH₂)_(m)—, -A-(CH₂)_(m)—; U is —R₅, —X—R₆ and * is achiral centre; and subjecting the resulting compound of Formula XXIIa orXXIIb to one or more of the following reactions: i) deprotecting thehydroxyl protecting groups to give the corresponding macrolide ofFormula XXIIIa,

 or ii) converting the 3-hydroxyl derivative of Formula XXIIb to3-ketone derivative of Formula XXIV,

iii) deprotecting the hydroxyl protecting groups of XXIV to give thecorresponding ketolide of Formula XXIIIb; f) Optionally, hydrogenatingthe compound obtained by any of the above steps to obtain thecorresponding saturated compound.
 17. The process of claim 16, whereinthe process of preparation of compound of Formula VII, comprisestreating a compound of Formula VI with hydroxylamine in a suitablesolvent

wherein: R₁ is hydrogen or methyl; R₂ is hydrogen or hydroxyl protectinggroup, wherein hydroxyl protecting groups are selected from the groupconsisting of triethylsilyl, trimethylsilyl, acetyl, benzoyl,methoxymethyl, benzyl, methoxyethoxymethyl or tertbutyldimethylsilyl;and Y′ is hydrogen and Y is OR₇ wherein R₇ is hydrogen or

wherein R_(2′) is hydrogen, (when R_(2′) is hydrogen, R₇ is designatedas cladinose) or hydroxyl protecting group, wherein hydroxyl protectinggroups are selected from the group consisting of triethylsilyl,trimethylsilyl, acetyl, benzoyl, methoxymethyl, methoxyethoxymethyl,benzyl or tertbutyldimethylsilyl; or Y and Y′ together with the carbonto which they are attached form C═O.
 18. The process of claim 17,wherein the process of preparation of compound of Formula VI comprisesthe steps of:

a) treating a compound of Formula IV with cyanoacetic acid in presenceof a base to give compound of Formula Va b) treating the compound ofFormula Va with a base to give compound of Formula VI wherein: R₁ ishydrogen or methyl; R₂ is hydrogen or hydroxyl protecting group, whereinhydroxyl protecting groups are selected from the group consisting oftriethylsilyl, trimethylsilyl, acetyl, benzoyl, methoxymethyl, benzyl,methoxyethoxymethyl or tertbutyldimethylsilyl; and wherein R_(2′) ishydrogen, (when R_(2′) is hydrogen R₇ is designated as cladinose) orhydroxyl protecting group, wherein hydroxyl protecting groups areselected from the group consisting of triethylsilyl, trimethylsilyl,acetyl, benzoyl, methoxymethyl, methoxyethoxymethyl, benzyl ortertbutyldimethylsilyl.